Aminopiperidine 4-oxo-4H-chromen-2-yl compounds

ABSTRACT

The invention relates to new compounds of formula I: ##STR1## in which: m represents zero, 1, 2, 3 or 4, 
     n and p represent zero, 1 or 2, 
     W represents an oxygen atom, an --NH-- radical, or a single bond, 
     R represents a 4-oxo-4H-chromen-2-yl radical, 
     R 1  represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, or an aryl radical, and 
     R 2  represents a hydrogen atom, an alkyl radical, an alkenyl radical, a cycloalkyl radical, a benzyl radical, a phenyl radical, an aralkyl radical, an alkoxyalkyl radical or a polyhalogenated alkyl radical, the optical isomers thereof and the addition salts thereof with a pharmaceutically acceptable organic or mineral acid, 
     and medicaments containing the same, are disclosed.

The present application is a division of our prior-filed copendingapplication Ser. No. 07/702,591, filed May 17, 1991.

The present invention relates to new aminopiperidine, aminopyrrolidineand aminoperhydroazepine compounds, to processes for the preparationthereof, and to pharmaceutical compositions containing them.

Certain 4-benzoylamino-1-cycloalkenylmethylpiperidine compounds havingdopamine antagonistic activity and serotonin receptor-stimulatingactivity are described in patent application FR-2 369 263. TheApplications EP-160 422, EP-256 798 and EP-277 794 describeN-aryl-N-(4-piperidyl)-amides having analgesic, anaesthetic and sedativeproperties.

The Application FR-2 370 731 describes amides derived from piperidinethat have the ability to neutralise the effects of dopamine ordopaminergic agents.

Certain amides derived from pyridine, tetrahydropyridine and piperidinethat have hypotensive, anti-inflammatory and analgesic activity aredescribed in GB-1410783, and certain N-aryl-N-piperidylarylacetamideshaving anti-arrhythmia properties are described in patent applicationFR-2 325 377.

The compounds of the invention are distinguished from other piperidine,pyrrolidine and perhydroazepine compounds described in the literature bytheir novel structures and their pharmacological properties.Pharmacological tests have shown that the compounds of the invention are5-HT_(1A) receptor antagonists. Some of them also have a good affinityto the sigma receptor. The compounds of the invention can therefore beused to treat pain, stress, migraine, anxiety, depression andschizophrenia.

The present invention relates more especially to compounds of formula I:##STR2## in which: m represents zero, 1, 2, 3 or 4,

n and p represent zero, 1 or 2,

W represents an oxygen atom, an --NH-- radical, or a single bond,

R represents

a 1,2-dihydro-2-oxo-1-phenyl-1,8-naphthyridin-3-yl radical of formula A##STR3## (in which R₃, R₄ and R₅, which may be the same or different,each represents a hydrogen atom, a halogen atom, an alkyl or alkoxyradical having from 1 to 6 carbon atoms, a hydroxy radical, apolyhalogenated alkyl radical having from 1 to 6 carbon atoms, or analkylthio radical having from 1 to 6 carbon atoms, and R₆ represents ahydrogen atom or a hydroxy radical),

a benzocyclobuten-1-yl radical of formula B: ##STR4## an indanyl radicalof formula C: ##STR5## a 2,3-dihydrobenzofuran-2-yl radical of formulaE: ##STR6## or a 4-oxo-4H-chromen-2-yl radical of formula F: ##STR7##(in which: R₇, R₈ and R₉, which may be the same or different, eachrepresents a hydrogen atom, a halogen atom, an alkyl or alkoxy radicalhaving from 1 to 6 carbon atoms, a polyhalogenated alkyl radical havingfrom 1 to 6 carbon atoms, or a hydroxy radical, or R₇ and R₈ or R₈ andR₉ together form a methylenedioxy radical, an ethylenedioxy radical, afuran ring or a dihydrofuran ring and

R₁₀ represents a hydrogen atom or an alkyl radical having from 1 to 6carbon atoms); R₁ represents a hydrogen atom or an alkyl radical havingfrom 1 to 6 carbon atoms or aryl radical, with the proviso, however,that when, simultaneously, R represents an indanyl radical, p representszero and W represents a single bond, R₁ does not represent an arylradical;

R₂ represents a hydrogen atom, an alkyl radical having from 1 to 6carbon atoms, an alkenyl radical having from 2 to 6 carbon atoms, acycloalkyl radical having from 4 to 7 carbon atoms, a benzyl radical ora phenyl radical (each optionally substituted by one or more halogenatoms, hydroxy radicals, or alkyl or alkoxy radicals having from 1 to 6carbon atoms), an aralkyl radical having from 7 to 12 carbon atoms, analkoxyalkyl radical having from 2 to 7 carbon atoms or a polyhalogenatedalkyl radical having from 1 to 6 carbon atoms, the optical isomersthereof and the addition salts thereof with a pharmaceuticallyacceptable organic or mineral acid.

The present invention also relates to a process for the preparation ofcompounds of the general formula I, characterised in that:

a) a compound of formula II

    R-(CH.sub.2).sub.m -X                                      (II)

in which R and m are as defined for formula I, and X represents ahalogen atom, a tosyloxy radical or a mesyloxy radical, is condensedwith a compound of formula III: ##STR8## in which n, p, R₁, W and R₂ areas defined for formula I, to yield compounds of formula I,

b) or a compound of formula IV: ##STR9## in which R₇, R₈, R₉ and R₁₀ areas defined above, m', represents 1, 2, 3 or 4, and q and s eachrepresent 0, 1 or 2, with the proviso, however, that q+s is equal to 1or 2, is reacted with a compound of formula V: ##STR10## in which n, p,R₁ are as defined for formula I, to yield a compound of formula VI:##STR11## in which R₁, R₇, R₈, R₉, R₁₀, n, p, q and s are as definedabove, and m' represents 1, 2, 3 or 4, which is subjected to the actionof lithium aluminium hydride to yield a compound of formula VII:##STR12## in which R₁, R₇, R₈, R₉, R₁₀, m', n, p, q and s are as definedabove,

which is subjected to the action of hydrogen in the presence of acatalyst such as PtO₂ or Pd/C, in an alcoholic solvent, in the presenceof a stoichiometric amount of hydrochloric or acetic acid, to yield acompound of formula VIII: ##STR13## in which R₁, R₇, R₈, R₉, R₁₀, m', n,p, q and s are as defined above,

which is then

α) reacted with a compound of formula IX: ##STR14## in which R₂ is asdefined for formula I but does not represent a hydrogen atom, and Wrepresents a single bond or an oxygen atom,

to yield compounds of formula I in which R represents a radical B or aradical C, W represents a single bond or an oxygen atom, R₂ is asdefined above but does not represent a hydrogen atom, and m is asdefined above with the exception of zero,

β) or reacted with formic acid in the presence of acetic anhydride toobtain compounds of formula I in which R represents a radical B or aradical C, W represents a single bond, R₂ represents a hydrogen atom,and m is as defined above with the exception of zero,

γ) or reacted with a compound of formula X:

    R.sub.2 --N═C═O                                    (X)

in which R₂ is as defined for formula I with the exception of a hydrogenatom, to yield compounds of formula I in which R represents a radical Bor a radical C, W represents an --NH-- radical, R₂ is as defined abovewith the exception of a hydrogen atom, and m is as defined above withthe exception of zero,

c) or a compound of formula XI: ##STR15##

in which R₃, R₄ and R₅ are as defined for formula A, is reacted, in thepresence of sodium hydride, with a compound of formula XII: ##STR16##

in which n, p, R₁, R₂ and W are as defined for formula I and R₁₁represents an alkyl radical having from 1 to 3 carbon atoms, to yieldcompounds of formula I in which R represents a radical of formula A, andm is 1,

which compounds of formula I are then, if desired:

converted into salts with a pharmaceutically acceptable organic ormineral acid, or

separated into their optical isomers and then converted into salts.

When R represents a radical of formula F, the compounds of formula IIare prepared from 2-hydroxyacetophenone derivatives and ethyl2-methylthioacetate (J. Org. Chem., (1984), 49, p. 5038).

When R represents a radical of formula E, the compounds of formula IIare prepared from suitable (2,3-dihydrobenzofuran-2-yl)-carboxylic acidderivatives (Chim. Ther., (1973), 3, p. 259). These compounds aresubjected to the action of lithium aluminium hydride to yield thecorresponding alcohols which enable compounds of formula II to beobtained by conventional methods.

When R represents a radical B, the compounds of formula II are obtainedfrom acids of formula XIII: ##STR17## in which R₇, R₈, R₉ and R₁₀ are asdefined above, and m' represents 1, 2, 3 or 4, in accordance with aprocess already described in the literature (J.A.C.S., (1975), 154, p.347). Processes for the preparation of acids of formula XIII or theirderivatives are also known (J.A.C.S., (1958), 80, p. 2257; J.A.C.S.,(1975), 157, p. 347; J. Chem., (1972), 32, p. 820; J. Org. Chem.,(1968), 33, p. 3327; Tet. Lett., (1973), 29, p. 73).

The piperidine compounds of formula III_(A) : ##STR18## in which R₁ isas defined for formula I and W and R₂ are as defined for formula IX, maybe prepared from 1-benzyl-4-oxopiperidine. That compound is subjected tothe action of an amine of formula XIV:

    H.sub.2 N--R.sub.1                                         (XIV)

in which R₁ is as defined for formula I, then to the action of sodiumborohydride dissolved in isopropanol, to yield compounds of formula XV:##STR19## in which R₁ is as defined for formula I.

The compounds of formula XV are then subjected to the action of acompound of formula IX in the presence of triethanolamine in methylenechloride to yield compounds of formula XVI: ##STR20## in which R₁ is asdefined for formula I and W and R₂ are as defined for formula IX.

The latter compounds are then subjected to catalytic hydrogenation toyield the desired compounds.

The piperidine compounds of formula V_(A) : ##STR21## in which R₁ is asdefined for formula I, are obtained from 1-acetyl-4-oxopiperidine. Thatcompound is reacted with an amine of formula XVII:

    H.sub.2 N--R.sub.1                                         (XVII)

in which R₁ is as defined for formula I, and then the reaction mixtureis subjected to catalytic hydrogenation to yield compounds of formulaXVIII: ##STR22## in which R₁ is as defined above.

The compounds of formula XVIII are then condensed with benzyl chloridein an alcohol, in the presence of sodium carbonate, to yield compoundsof formula XIX: ##STR23## in which R₁ is as defined for formula I. Thelatter compounds are then subjected to the action of hydrochloric acidin methanol to yield compounds of formula V_(A).

The compounds of formula XII are obtained by conventional methods(Michael reaction).

The optical isomers of compounds of formula I to which the presentinvention also relates can be obtained by conventional methods(conversion into salts with an optically active acid).

Among the pharmaceutically acceptable acids for the preparation ofaddition salts of compounds of the general formula I the following maybe mentioned: phosphoric, hydrochloric, citric, hydriodic, oxalic,maleic, sulphuric, tartaric, mandelic, fumaric and methanesulphonic acidetc. . .

The compounds of the invention and the addition salts thereof exhibitvery valuable pharmacological properties. Pharmacological tests haveshown that the compounds of the invention behave like very powerfulantagonists for 5-HT_(1A) serotonin receptors, having an antagonisticactivity in the central nervous system.

Moreover, some of then are good ligands for the sigma receptor.

The compounds of the invention are therefore used for the treatment ofstress (Neuropharmac., (1989), Vol. 25, No. 5, p. 471-476), migraine(T.I.P.S., (1989), Vol. 10, pp. 200-204), anxiety, depression,schizophrenia and pain [Pharmacology and Toxicology, (1989), 64, p. 3-5;Drugs of the future, (1988), 13, No. 5, p. 429-437; J. Neurol. Transm.,(1988), 74, p. 195-198].

The compounds, which are active with respect to 5-HT_(1A) receptors, mayalso modify alimentary and sexual behaviour (J. of Receptor Research,(1988), 8, p. 59-81).

The pharmacological properties of sigma ligands are illustratedgenerally especially by: WALKER J. MICHAEL et al., PharmacologicalReviews (1990), 42 (4), 355-402, and in the field of analgesia by:Trends in Neurosci. (1987), 10, 444-446; Clin. Neuropharmacol. (1988),11, 105 and Mol. Pharmacol. (1987), 32, 772-784.

The sigma ligands also serve to modulate the action of a variety ofneurotransmitters--cf. Eur. J. Pharmacol. (1988), 149, 399-400.

1,3-ditolylguanidine and its derivatives have been used in the diagnosisand treatment of hallucinations associated with mental psychoses, cf.Trends in Neurosci. (1988), 11, 37-40.

The invention extends also to pharmaceutical compositions comprising asactive ingredient at least one compound of the general formula I, or asalt thereof with a pharmaceutically acceptable organic or mineral acid,in association with one or more appropriate inert excipients.

The pharmaceutical compositions so obtained are advantageously presentedin various forms, such as, for example, in the form of tablets, dragees,soft gelatin capsules, suppositories, and injectable or drinkablesolutions.

The dosage can vary widely depending on age, the weight of the patient,the nature and severity of the disorder and the administration route.Generally, a single dose will range from 0.1 to 100 mg, and the dailydose for the treatment of humans from 0.1 to 500 mg. The preferred routeof administration is the oral or parenteral route.

The following Examples, which are not limiting, illustrate theinvention.

Melting points, unless specified otherwise, were measured according tothe Micro-Kofler method.

The proton nuclear magnetic resonance spectra of the compounds of thegeneral formula I were recorded at 200 or 400 MHz, as the case may be,and are indicated in Table I.

EXAMPLE 1N-{1-[(4-oxo4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylpropionamidehydrochloride Stage A 1-benzyl-4-methylaminopiperidine dihydrochloride

A freshly prepared solution of 15 g of monomethylamine in 45 ml ofethanol is poured onto 29.7 g of 1-benzyl-4-oxopiperidine in 340 ml ofisopropanol that has been cooled to 5° C. and the mixture is left for 2hours at 10° C.

10.5 g of sodium hydroxide solution are added and left for 1 hour atroom temperature to dissolve. The mixture is adjusted to 10° C. and 8.1g of sodium borohydride are added. The mixture is left overnight withstirring. The solvents are evaporated, the residue is taken up in waterand extracted with ether, and the ethereal extract is dried overanhydrous sodium sulphate. This ethereal phase is filtered and thenacidified with ethereal hydrogen chloride. The salt that precipitates isfiltered off and dried to yield the desired product.

Yield: 77%.

Melting point: >260° C.

Proton nuclear magnetic resonance spectrum (solvent D₂ O): 7.55 ppm, 5H,s: 4.35 ppm, 2H, s; 3 to 3.09 ppm, 5H, m; 2.75 ppm, 3H, s; 1.5 to 2.6ppm, 4H, m.

Stage B N-(1-benzylpiperid-4-yl)-N-methylpropionamide

11 g of propionyl chloride are added dropwise to 33 g of the compoundobtained in the above Stage in 300 ml of methylene chloride and 50.5 mlof triethylamine cooled to 5° C. The mixture is left at 0° C. for 1hour, transferred to a flask, washed with water, dried and evaporated toyield the desired product.

Yield: 88%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 ppm, 5H,s; 3.5 ppm, 2H, s; 3.3 to 2.8 ppm, 4H, m+s; 1.4 to 2.7 ppm, 10H, q+m+m;1.1 ppm, 3H, t.

Stage C N-piperid-4-yl-N-methylpropionamide

31 g of the amine obtained in Stage B are hydrogenated in 350 ml ofethanol with 1 g of palladium hydroxide at atmospheric pressure and roomtemperature. The mixture is filtered and evaporated to yield the desiredproduct in the form of an oil.

Yield: 60%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 3.5 to 2ppm, 10H, m+s+m+q+1H exchangeable; 1.3 to 1.9 ppm, 4H, m; 1.1 ppm, 3H,t.

Stage D

6.3 g of (4-oxo-4H-chromen-2-yl)-methyl iodide, 3.7 g of the compoundobtained in the above Stage, and 3ml of the triethylamine in 70 ml ofdimethylformamide are heated at 60° C. for 4 hours with stirring. Thesolvent is then evaporated off, the residue taken up in diethyl etherand washed with iced water, and the ethereal solution dried andevaporated. The resulting oil is purified by flash chromatography usinga mixture of ethyl acetate and methanol (95:5 v/v) as solvent.

Yield: 36%.

2.5 g of the base obtained in this manner are dissolved in 5 ml ofethanol. 1.5 ml of 5N ethereal hydrogen chloride are added, theprecipitate is filtered off and dried to yieldN-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylpropionamidehydrochloride.

Yield: 72%.

Melting point: 220°-222° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            62.55   62.15                                                  H %            6.91    6.69                                                   N %            7.68    7.61                                                   Cl %           9.72    9.52                                                   ______________________________________                                    

EXAMPLE 2N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylbutanamideStage A N-(1-benzylpiperid-4-yl)-N-methylbutanamide

This compound was obtained from 1-benzyl-4-methylaminopiperidinedihydrochloride and butyryl chloride in accordance with the processdescribed in Stage B of Example 1.

Yield: 82%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 ppm, 5H,m; 4.6 ppm, 1H, m; 3.5 ppm, 2H, s; 3 ppm, 2H, t; 2.8 ppm 3H, s; 2.3 ppm,2H, t; 1.7 ppm, 2H, m; 1.6 ppm, 3H, t; 1.5 to 2.3 ppm, 6H, m.

Stage B N-piperid-4-yl-N-methylbutanamide

This compound was obtained from the compound described in the aboveStage and in accordance with the process described in Stage C ofExample 1. The hydrogenation was carried out at 40° C. under 40 Kg.

Yield: 64%.

Proton nuclear magnetic resonance spectrum solvent CDCl₃): 4.65 ppm, 1H,m; 3.2 ppm, 2H, m; 2.9 to 2.85 ppm 3H, 2s; 2.9 to 2.6 ppm, 2H, m; 2.3 to2.35 ppm, 2H, 2t; 1.6 to 1.85 ppm, 6H, m; 1 ppm, 3H, 2t; 2.6 ppm, 1H, sbroad.

Stage C

N-{1-[(4-oxo-4H-chromen-2-yl)-methyl[-piperid-4-yl}-N-methylbutanamidewas obtained in accordance with the process described in Stage D ofExample 1 from (4-oxo-4H-chromen-2-yl)-methyl iodide and the compoundobtained in the above Stage.

Yield: 20%.

Melting point: 127°-130° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      70.15         70.31   69.99                                          H %      7.65          7.68    7.65                                           N %      8.18          7.90    7.96                                           ______________________________________                                    

EXAMPLE 3N-{1-[4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylacetamide

This compound was prepared in accordance with the process described inExample 1 but using acetyl chloride instead of propionyl chloride inStage B.

Yield: 15%.

Melting point: 118°-120° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            68.17   68.63                                                  H %            7.05    7.13                                                   N %            8.91    8.73                                                   ______________________________________                                    

EXAMPLE 4N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-ethylpropionamidehydrochloride

This compound was prepared in accordance with a process equivalent tothat described in Example 1, but replacing monomethylamine bymonoethylamine in Stage A.

Yield (base): 45%.

Yield (salt): 80%.

Melting point (salt): 230°-232° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      63.40         63.28   63.11                                          H %      7.18          7.08    7.05                                           N %      7.39          7.36    7.35                                           Cl %     9.36          9.36    9.35                                           ______________________________________                                    

EXAMPLE 5N-{1-[2-(4-oxo-4H-chromen-2-yl)-ethyl]-piperid-4-yl}-N-methylpropionamidehydrochloride Stage AN-{1-[2-(ethoxycarbonyl)-ethyl]-piperid-4-yl}-N-methylpropionamide

14 g of ethyl acrylate in 45 ml of ethanol are added dropwise to 23.8 ofthe amine obtained in Stage C of Example 1 dissolved in 45 ml ofethanol. The mixture is stirred at room temperature for 3 hours,evaporated, and the residual oil is distilled in a Kugelrohr (bulb tube)at 120° C. and 0.09 mm Hg.

Yield: 90%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 4.5+3.6 ppm,1H, m; 4.2 ppm, 2H, q; 3 ppm, 2H, m; 2.85 ppm, 3H, 2s; 2.7 ppm, 2H, t;2.5 ppm, 2H, t; 2.35 ppm, 2H, 2q; 2.1 ppm, 2H, m; 1.5 to 2 ppm, 4H, m;1.25 ppm, 3H, t; 1.15 ppm, 3H, 2t.

Stage BN-{1-[3,5-dioxo-5-(2-hydroxyphen-1-yl)-pent-1-yl]-piperid-4-yl}-N-methylpropionamidehydrochloride

A mixture comprising 34 g of the compound obtained in the above Stage,and 16.3 g of ortho-hydroxyacetophenone dissolved in 90 ml of dioxane,are poured onto 14.4 g of 60% sodium hydride in 120 ml of dioxanepreheated to 80° C. The mixture is left for 1 hour at 80° C., dilutedwith water and acidified in the cold. The precipitate is filtered offand dried to yield the desired compound.

Yield: 22%.

Melting point: >260° C.

Proton nuclear magnetic resonance spectrum (solvent D₂ O+NaOD): 7.15ppm, 2H, m; 6.6 ppm, 1H, d; 6.5 ppm, 1H, t; 4.3 and 3.75 ppm, 1H, 2m;3.0 to 2.55 ppm, 9H, m; 2.55 to 2.3 ppm, 4H, m+t+q; 2.2 ppm, 2H, m; 1.95to 1.5 ppm, 4H, m; 1.1 ppm, 3H, 2t.

Stage C

2.5 g of the compound obtained in Stage B are stirred for one night with25 ml of 3.7N methanolic hydrogen chloride.

The mixture is filtered and the residue is dried over potassiumhydroxide to yieldN-(1-[2-(4-oxo-4H-chromen-2-yl)-ethyl]-piperid-4-yl}-N-methylpropionamidehydrochloride.

Yield: 65%.

Melting point: 248°-250° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            63.40   63.71                                                  H %            7.18    7.02                                                   N %            7.39    7.33                                                   Cl %           9.36    9.61                                                   ______________________________________                                    

EXAMPLE 6 EthylN-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylcarbamatehydrochloride Stage A Ethyl N-(1-benzylpiperid-4-yl)-N-methylcarbamate

This compound was prepared from the compound described in Stage A ofExample 1, in accordance with the process described in Stage B ofExample 1 but replacing propionyl chloride with ethyl chloroformate.

Yield: 89%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 ppm, 5H,m; 4.1 ppm, 2H, q; 4 ppm, 1H, m; 3.5 ppm, 2H, s; 2.95 ppm, 2H, m; 2.8ppm, 3H, s; 2.1 ppm, 2H, m; 1.9 to 1.5 ppm, 4H, m; 1.25 ppm, 3H, t.

Stage B Ethyl N-piperid-4-yl-N-methylcarbamate

49 g of the compound obtained in Stage A dissolved in 500 ml of aceticacid in the presence of 1 g of 5% Pd/C are hydrogenated at 50° C. under5 Kg. The catalyst is filtered off, the filtrate is evaporated,recovered with diethyl ether and rendered basic in the cold with 50 mlof sodium hydroxide solution. The ethereal phase is dried and evaporatedto yield the desired compound.

Yield: 61%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 4.15 ppm,2H, q; 3.9-4.2 ppm, 1H m; 3.15 ppm, 2H, m; 2.8 ppm, 3H, s; 2.65 ppm, 2H,m; 1.6 ppm, 4H, m; 1.25 ppm, 3H, 1H exchangeable.

Stage C

EthylN-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylcarbamate isobtained from the compound described in Stage B and in accordance withthe process described in Stage D of Example 1.

Yield: 65%.

4.3 g of this base are dissolved in 20 ml of acetonitrile and 3.5 ml of3.8N ethereal hydrogen chloride are added to obtain ethylN-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylcarbamatehydrochloride.

Yield: 73%.

Melting point: >260° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      59.92         59.73   59.52                                          H %      6.62          6.58    6.59                                           N %      7.36          7.06    7.10                                           Cl %     9.31          9.30    9.09                                           ______________________________________                                    

EXAMPLE 7N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylisobutylamidehydrochloride

This compound was obtained in accordance with the process described inExample 1 but replacing propionyl chloride with isobutyl chloride inStage B.

Yield (base): 65%.

Yield (salt): 67%.

Melting point (salt): 248°-250° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      63.40         63.28   63.34                                          H %      7.18          7.22    7.28                                           N %      7.39          7.40    7.44                                           Cl %     9.36          9.48    9.30                                           ______________________________________                                    

EXAMPLE 8 Methyl[1-benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride Stage A Methyl N-(1-benzylpiperid-4-yl)-N-methylcarbamate

This compound was prepared in accordance with the process described inStage B of Example 1 using methyl chloroformate instead of propionylchloride.

Yield: 71%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 ppm, 5H,m; 3.7 to 4.1 ppm, 1H m; 3.7 ppm, 3H, s; 3.5 ppm, 2H, s; 2.95 ppm, 2H,d; 2.75 ppm, 3H, s; 2.1 ppm, 2H, t; 1.5 to 1.9 ppm, 4H, m.

Stage B Methyl N-piperid-4-yl-N-methylcarbamate

The carbamate described in the above Stage is subjected to hydrogenationunder 5 Kg at 50° C. in ethanol in the presence of 5% Pd/C and asuitable amount of concentrated hydrochloric acid to yield thecorresponding hydrochloride. Conversion to the base in the presence ofdiethyl ether and 40% sodium hydroxide solution yields the desiredcompound.

Yield: 53%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 4.1 ppm, 1H,m; 3.7 ppm, 3H, s; 3.15 ppm, 2H, m; 2.8 ppm, 3H, d; 2.6 to 2.9 ppm, 2H,m; 1.5 to 1.7 ppm, 4H, m; 1.75 ppm, 1H exchangeable.

Stage C

7.3 g of 1-iodomethylbenzocyclobutene (prepared in accordance with theprocess described in patent application FR 89.14571 of 7th of November1989) and 5.1 g of the compound obtained in Stage B in 100 ml ofdimethylformamide are heated at 60° C. for 6 hours with stirring.

The solvent is evaporated, the residue is taken up in water, extractedwith diethyl ether and then the ethereal phase is extracted with Nhydrochloric acid. The extract is rendered basic in the cold andextracted with diethyl ether to yield methylN-[1-benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamate.

Yield: 43%.

3.7 g of this base dissolved in 30 ml of ethanol are converted into asalt with 10 ml of 3N ethereal hydrogen chloride to yield thecorresponding hydrochloride.

Yield: 59%.

Melting point: >260° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      62.86         62.85   62.51                                          H %       7.76          7.95    7.70                                          N %       8.62          8.57    8.43                                          Cl %     10.91         10.97   10.54                                          ______________________________________                                    

EXAMPLE 9 PropylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride

This compound was obtained in accordance with the process described inExample 8 but using propyl chloroformate instead of methyl chloroformatein Stage A.

Yield (base): 28%.

Yield (salt): 73%.

Melting point: 248°-250° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      64.67         64.35   64.18                                          H %       8.28          8.48    8.40                                          N %       7.94          7.95    7.93                                          Cl %     10.05         10.17   10.05                                          ______________________________________                                    

EXAMPLE 10N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylpentafluoropropionamidehydrochloride

This compound was prepared in accordance with the process described inExample 8 but using pentafluoropropionyl chloride instead of methylchloroformate in Stage A.

Yield (salt): 10.5%.

Melting point: 246°-248° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      52.37         52.56   52.56                                          H %      5.37          5.54    5.53                                           N %      6.79          6.78    6.68                                           Cl %     8.59          8.85    8.49                                           ______________________________________                                    

EXAMPLE 11 Tert-butylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride Stage A Tert-butylN-(1-benzylpiperid-4-yl)-N-methylcarbamate

24 g of tert-butyl pyrocarbonate are poured onto 27.8 g of the amineobtained in Stage A of Example 1 in 200 ml of dioxane and 200 ml of 1Nsodium hydroxide solution while maintaining the temperature at 5° C. Themixture is left for one hour at 5° C. and then extracted with diethylether.

The residual oil is subjected to flash chromatography using a mixture ofmethylene chloride and ethyl acetate (80:20 v/v) as solvent to yield thedesired compound.

Yield: 66%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 ppm, 5H,m; 4.2 to 3.7 ppm, 1H, s; 3.5 ppm, 2H, s; 2.95 ppm, 2H, m; 2.75 ppm, 3H,s; 2.05 ppm, 2H, m; 1.9 to 1.55 ppm, 4H, m; 1.45 ppm, 9H, s.

Stage B Tert-butyl N-piperid-4-yl-N-methylcarbamate

20 g of the compound obtained in the above Stage, in 200 ml of ethanoland 3.6 g of acetic acid are subjected to hydrogenation with 2 g of 5%Pd/C under 5 Kg at 50° C.

After evaporation, removal of the acetate with sodium hydroxide solutionin the presence of diethyl ether and decanting, the residue is dried andevaporated to yield the desired compound.

Yield: 71%.

Melting point: <50° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 4 ppm, 1H,m; 3.1 ppm, 2H, m; 2.7 ppm, 3H, s; 2.6 ppm, 2H, m; 1.4 to 1.7 ppm, 4H,m; 1.45 ppm, 9H, s; 1.65 ppm, 1H exchangeable.

Stage C

Tert-butylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride is obtained in accordance with the process described inStage C of Example 8 from 1-iodomethylbenzocyclobutene and tert-butylN-piperid-4-yl-N-methylcarbamate.

Yield: 60%.

Melting point: >260° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            65.47   64.97                                                  H %            8.52    8.63                                                   N %            7.63    7.53                                                   Cl %           9.66    9.84                                                   ______________________________________                                    

EXAMPLE 12 PhenylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride

This compound was prepared in accordance with the process described inExample 8 but using phenyl chloroformate instead of propionyl chloridein Stage A.

Yield: 21%.

Melting point: 262°-264° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      68.29         67.71   67.76                                          H %      7.03          7.52    7.08                                           N %      7.24          7.01    6.98                                           Cl %     9.16          9.16    9.09                                           ______________________________________                                    

EXAMPLE 13 EthylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-ethylcarbamatehydrochloride

This compound was prepared in accordance with the process described inExample 8 but from 1-benzyl-4-ethylaminopiperidine dihydrochloride andreplacing the methyl chloroformate with ethyl chloroformate in Stage A.

Yield: 13%.

Melting point: 258°-260° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      64.67         64.42   64.51                                          H %       8.28          8.69   8.69                                           N %       7.94          7.83   7.75                                           Cl %     10.05         10.25   9.96                                           ______________________________________                                    

EXAMPLE 14 MethylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-ethylcarbamatehydrochloride

This compound was prepared in accordance with the process described inExample 8 using 1-benzyl-4-ethylaminopiperidine and methyl chloroformatein Stage A.

Yield: 13%.

Melting point: 258°-260° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      63.80         63.92   63.71                                          H %       8.03          8.34    8.18                                          N %       8.27          8.07    8.10                                          Cl %     10.46         10.57   10.39                                          ______________________________________                                    

EXAMPLE 15 IsobutylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatefumarate

The base was prepared also in accordance with the process described inExample 8 using isobutyl chloroformate instead of methyl chloroformatein Stage A.

The isobutylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamate soobtained is then converted into a salt with an appropriate amount offumaric acid in ethanol.

Yield: 27%.

Melting point: 190°-192° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      64.55         64.60   64.50                                          H %      7.67          7.94    7.82                                           N %      6.29          6.31    6.35                                           ______________________________________                                    

EXAMPLE 16 N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-propionamidehydrochloride Stage A 1-benzyl-4-hydroxyiminopiperidine

18.9 g of 1-benzyl-4-oxopiperidine, 26.8 g of hydroxylaminehydrochloride, and 24.8 g of sodium acetate in 200 ml of ethanol arestirred for 8 hours.

The mixture is concentrated, taken up in 100 ml of water and renderedbasic and the resulting precipitate is filtered off.

Yield: 98%.

Melting point: 125°-127° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 ppm, 5H,m; 3.55 ppm, 2H, s; 2.75 to 2.4 ppm, 6H, m; 2.35 ppm, 2H, m; 3 ppm, 1Hexchangeable.

Stage B 4-amino-1-benzylpiperidine

9.3 g of the oxime obtained in the above Stage are hydrogenated in 230ml of ethanol and 9.3 ml of ammonia in the presence of Raney nickel atatmospheric pressure and at room temperature.

The desired compound is obtained after filtering off the catalyst andevaporating the solvent.

Yield: 80%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 ppm, 5H,m; 3.4 ppm, 2H, s; 2.8 ppm, 2H, m; 2.6 ppm, 1H, m; 2 ppm, 2H, m; 1.8ppm, 2H, m; 1.4 ppm, 2H, m; 1.4 ppm, 2H exchangeable.

Stage C N-(1-benzylpiperid-4-yl)-propionamide

7.5 g of propionyl chloride are added dropwise to 10 g of aminedescribed in Stage B in 100 ml of benzene and 7.7 ml of triethylamine.

The mixture is decanted to a separating funnel, diluted with diethylether, washed with water, dried and evaporated.

Yield: 83%.

Melting point: 105°-107° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.25 ppm,5H, m; 4.8 and 3.7 ppm, 1H, 2m; 3.5 ppm, 2H, s; 2.8 ppm, 2H, m; 2.1 ppm,2H, q; 2.1 ppm, 2H, m; 1.9 ppm, 2H, m; 1.45 ppm, 2H, m; 1.15 ppm, 3H, t;5.35 ppm, 1H exchangeable.

Stage D N-piperid-4-ylpropionamide acetate

The debenzylation of the amide obtained in Stage C is carried out inaccordance with the method described in Stage B of Example 11 to yieldthe desired acetate after evaporation and solidification with diethylether.

Yield: 48%.

Melting point: 128°-130° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 8.35 ppm, 2Hexchangeable; 6.65 ppm, 1H exchangeable; 3.95 ppm, 1H, m; 3.3 ppm, 2H,m; 2.35 ppm, 2H, td; 2.2 ppm, 2H, q; 1.95 ppm, 3H, s; 2.1 to 1.6 ppm,4H, m; 1.1 ppm, 3H, t.

Stage E

N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-propionamidehydrochloride was prepared in accordance with the process described inStage C of Example 8 from N-piperidin-4-ylpropionamide acetate and1-iodomethylbenzocyclobutene.

Yield: 17%.

Melting point: 262°-264° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            66.11   65.87                                                  H %             8.16    8.35                                                  N %             9.07    9.03                                                  Cl %           11.48   11.57                                                  ______________________________________                                    

EXAMPLE 17 2-methoxyethylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride

This compound was prepared in accordance with the process described inExample 11 (Stages B and C) but using 2-methoxyethylN-(1-benzylpiperid-4-yl)-N-methylcarbamate in Stage B. The latter isobtained in accordance with the process described in Stage B of Example1 using methoxyethyl chloroformate instead of propionyl chloride.

Yield: 14%.

Melting point: 210°-212° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory      Found                                                      ______________________________________                                        C %      61.86         61.81   61.69                                          H %      7.92          7.92    8.03                                           N %      7.59          7.51    7.23                                           Cl %     9.61          9.78    9.53                                           ______________________________________                                    

EXAMPLE 18 CyclohexylN-[(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride

This compound was prepared in accordance with the process described inStages B and C of Example 11, but using cyclohexylN-(1-benzylpiperid-4-yl)-N-methylcarbamate in Stage B. The latter isobtained in accordance with the process described in Stage B of Example1 using hexyl chloroformate.

Yield: 13%.

Melting point: 262°-264° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory       Found                                                    ______________________________________                                        C %       67.24          66.77  66.72                                         H %       8.46           8.53   8.64                                          N %       7.13           7.35   7.33                                          Cl %      9.02           8.48   8.57                                          ______________________________________                                    

EXAMPLE 19 BenzylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride Stage A 1-acetyl-4-methylaminopiperidine

9.9 g of methylamine in 50 ml of ethanol are added to 14.4 g of1-acetyl-4-oxopiperidine in 100 ml of ethanol. The mixture is thenhydrogenated in the presence of platinum oxide at room temperature andatmospheric pressure, filtered and evaporated.

Yield: 98%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 4.4 to 3.7ppm, 2H, m; 3.1 to 2.7 ppm, 2H, s; 2.6 ppm, 1H, m; 2.45 ppm, 3H, s; 2.05ppm, 3H, s; 1.35 and 1.2 ppm, 4H, m; 1.7 ppm, 1H exchangeable.

Stage B Benzyl N-(1-acetylpiperid-4-yl)-N-methylcarbamate

The amine obtained in Stage A is treated with benzyl chloroformate inaccordance with the process described in Stage B of Example 1 to obtainthe desired carbamate.

Yield: 54%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.35 ppm,5H, m; 5.1 ppm, 2H, s; 4.75 ppm, 1H, m; 4.2 ppm, 1H, m; 3.85 ppm, 1H, m;3.1 ppm, 1H, t; 2.8 ppm, 3H, s; 2.55 ppm, 1H, t; 2.1 ppm, 3H, s; 1.8 to1.4 ppm, 4H, m.

Stage C Benzyl N-piperid-4-yl-N-methylcarbamate hydrochloride

14.5 g of the compound obtained in Stage B are refluxed with 50 ml ofmethanol and 30 ml of 6N hydrochloric acid for 20 hours. Afterevaporation the hydrochloride of the desired product is obtained.

Yield: 83%.

Melting point: 203°-205° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.4 ppm, 5H,m; 5.15 ppm, 2H, s; 4.3 ppm, 2H, m; 3.6 ppm, 2H, d; 2.95 ppm, 2H, m;2.85 ppm, 3H, s; 2.25 ppm, 2H, m; 1.85 ppm, 2H, d.

Stage D

Benzyl N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-ethylcarbamatehydrochloride was prepared from benzyl N-piperid-4-yl-N-methylcarbamatehydrochloride and 1-iodomethylbenzocyclobutene, in accordance with theprocess described in Stage C of Example 8, in the presence oftriethylamine.

Yield: 22.5%.

Melting point: 210°-212° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory       Found                                                    ______________________________________                                        C %       68.90          68.84  68.97                                         H %       7.29           7.43   7.55                                          N %       6.99           7.06   7.08                                          Cl %      8.84           9.00   8.79                                          ______________________________________                                    

EXAMPLE 20N-{1-[(1-methylbenzocyclobuten-1-yl)-methyl]-piperid-4-yl}-N-methylpropionamidehydrochloride

This compound was obtained from 1-methyl-1-iodomethylbenzocyclobutene(prepared in accordance with the process described in patent applicationFR 89.14571 of 7th November 1989) andN-piperid-4-yl-N-methylpropionamide in accordance with the processdescribed in Stage C of Example 8.

Yield: 14.5%.

Melting point: 222° C.

    ______________________________________                                        Elemental analysis:                                                                         Theory                                                                              Found                                                     ______________________________________                                        C %             67.74   67.43                                                 H %             8.68    8.59                                                  N %             8.31    8.24                                                  Cl %            10.52   10.65                                                 ______________________________________                                    

EXAMPLE 21N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-ethylacetamidehydrochloride

3.3 g of N-piperid-4-yl-N-ethylacetamide and 2.8 g of1-methylbenzocyclobutene tosylate (prepared in accordance with theprocess described in J.A.C.S., (1975), 154, p. 347) are refluxed undernitrogen for 20 hours in 16 ml of toluene. After cooling, the reactionmixture is evaporated to dryness and taken up in diethyl ether. Afterextraction with N hydrochloric acid, the extract is rendered basic inthe presence of diethyl ether and the organic phase is washed withwater, dried over magnesium sulphate and evaporated in vacuo to yieldN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-ethylacetamide. Thecorresponding hydrochloride is obtained in ethyl acetate in the presenceof ethereal hydrogen chloride.

Yield: 20.7%.

Melting point: 265°-267° C.

    ______________________________________                                        Elemental analysis:                                                                         Theory                                                                              Found                                                     ______________________________________                                        C %             66.96   67.08                                                 H %             8.43    8.55                                                  N %             8.68    8.59                                                  Cl %            10.98   11.02                                                 ______________________________________                                    

EXAMPLE 22N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylpropionamidehydrochloride

This compound was prepared in accordance with the process described inExample 21 using N-piperid-4-yl-N-methylpropionamide as amide.

Yield: 28%.

Melting point: 302°-306° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory       Found                                                    ______________________________________                                        C %       66.96          66.67  67.00                                         H %       8.43           8.24   8.10                                          N %       8.68           8.62   8.66                                          Cl %      10.98          10.87  10.87                                         ______________________________________                                    

EXAMPLE 23 EthylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride

This compound was prepared in accordance with the process described inExample 21 using ethyl N-piperid-4-yl-N-methylcarbamate instead ofN-piperid-4-yl-N-ethylacetamide.

Yield: 58%.

Melting point: 305°-313° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory       Found                                                    ______________________________________                                        C %       63.80          63.55  63.84                                         H %       8.03           7.80   8.00                                          N %       8.27           8.44   8.49                                          Cl %      10.46          10.78  10.78                                         ______________________________________                                    

EXAMPLE 24N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylbutyramidehydrochloride

4 g of the compound obtained in Stage B of Example 2 and 3.1 g of1-methylbenzocyclobutene tosylate are refluxed under nitrogen for 18hours in 20 ml of toluene. After cooling, the reaction mixture isevaporated to dryness and taken up in diethyl ether.

After extraction with N hydrochloric acid, the extract is rendered basicin the presence of diethyl ether, and the organic phase is washed withwater and dried over magnesium sulphate. After evaporation of thesolvent in vacuo, the base obtained is taken up in ethyl acetate andtreated with ethereal hydrogen chloride to obtain the desired compound.

Yield: 47%.

Melting point: 238° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory       Found                                                    ______________________________________                                        C %       67.74          67.48  67.55                                         H %       8.68           8.83   8.86                                          N %       8.31           8.24   8.28                                          Cl %      10.52          10.59  10.45                                         ______________________________________                                    

EXAMPLE 25 AllylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride. Stage A N-(1-acetylpiperid-4-yl)-N-benzylmethylamine

A mixture containing 0.5 mol of the compound obtained in Stage A ofExample 19, 0.5M benzyl chloride and 1M sodium carbonate in 650 ml ofethanol is refluxed for one night. The precipitate formed is filteredoff, the solvent is evaporated, the evaporation residue is taken up in1N hydrochloric acid and extracted with diethyl ether, and the etherealextract is rendered basic with sodium hydroxide solution and extractedwith ethyl acetate to obtain the desired compound.

Yield: 65%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.25 ppm,5H, m; 4.6 ppm, 1H, m; 3.8 ppm, 1H, m; 3.55 ppm, 2H, s; 3 ppm, 1H, td;2.7 to 2.4 ppm, 2H, m; 2.2 ppm, 3H, s; 2.05 ppm, 3H, s; 1.85 ppm, 2H, m;1.55 ppm, 2H, m.

Stage B 4-(N-benzyl-N-methylamino)-piperidine

80 g of the compound obtained in the above Stage dissolved in 375 ml ofmethanol are treated with 97.5 ml of concentrated hydrochloric acid and97.5 ml of water for 2 hours under reflux. The reaction solution isevaporated and rendered basic and extracted with diethyl ether to obtainthe desired compound.

Yield: 85.5%.

Stage C1-(benzocyclobuten-1-ylcarbonyl)-4-(N-benzyl-N-methylamino)-piperidine

41 g of carbonyldiimidazole are added to a solution of 36.2 g ofbenzocyclobuten-1-ylcarboxylic acid in 400 ml of methylene chloride. Themixture is stirred for 4 hours and the compound obtained in the aboveStage, dissolved in methylene chloride, is added. The reaction mixtureis refluxed for 72 hours, diluted with 1500 ml of diethyl ether andextracted 3 times with 100 ml of 0.1N hydrochloric acid. The aqueousphases are removed and the organic phase is re-extracted three timeswith 100 ml of 1N hydrochloric acid. The acidic aqueous phases are thenrendered basic and extracted with diethyl ether to obtain the desiredcompound.

Yield: 34%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.4 to 7ppm, 9H, m; 4.65 ppm, 1H, m; 4.45 ppm, 1H, m; 4.15 ppm, 1H, m; 3.6 ppm,2H, s; 3.6 to 3.3 ppm, 2H, m; 3.15 ppm, 1H, m; 2.8 to 2.5 ppm, 1H+1H, m;2.25 ppm, 3H, s; 2 ppm, 2H, m; 1.8 to 1.4 ppm, 2H, m.

Stage D1-{[4-(N-benzyl-N-methylamino)-piperid-1-yl]-methyl}-benzocyclobutene

28 g of the compound obtained in Stage C dissolved in 150 ml oftetrahydrofuran are poured onto a suspension of 3.2 g of lithiumaluminium hydride in 50 ml of tetrahydrofuran. The reaction mixture isrefluxed for 3 hours, treated in customary manner, filtered, and theorganic phase is evaporated to isolate the desired compound.

Yield: 84.5%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 to 6.9ppm, 9H, m; 3.7 ppm, 1H, m; 3.55 ppm, 2H, s; 3.35 ppm, 1H, dd; 3.1 ppm,2H, m; 2.8 ppm, 1H+1H, m; 2.6 to 2.4 ppm, 2H, m; 2.2 ppm, 3H, s; 2.05ppm, 2H, m; 1.9 to 1.6 ppm, 4H, m.

Stage E 1-[(4-methylaminopiperid-1-yl)-methyl]-benzocyclobutene

22 g of the compound obtained in Stage D in 220 ml of ethanol and 4.2 mlof acetic acid containing 2.2 g of 5% Pd/C are hydrogenated at 50° C.under 5 atmospheres. The catalyst is removed by filtration, the filtrateis evaporated and then coagulated by stirring with 20 ml of diethylether and then the product is rendered alkaline with 20% sodiumhydroxide in the presence of 200 ml of diethyl ether, in order toprecipitate the desired product.

Yield: 77%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.4-7 ppm,4H, m; 3.75-3.6 ppm, 1H, m; 3.45 to 3.25 ppm, 1H, m; 3.05 to 2.9 ppm,2H, m; 3 to 2.5 ppm, 1H+1H, m; 2.45 ppm, 3H, s; 2.2 to 2 ppm, 2H, m; 2.0to 1.8 ppm, 2H, m; 1.55 to 1.3 ppm, 2H, m; 2 to 1.7 ppm, 1Hexchangeable; 2.8 ppm, 1H, m; 2.5 to 2.3 ppm, 1H, m.

Stage F

1.4 ml of allyl chloroformate dissolved in 5 ml of benzene are pouredonto 1.8 ml of triethylamine and 3 g of the compound obtained in theabove Stage dissolved in 30 ml of benzene. The mixture is diluted withdiethyl ether, washed with water, dried and evaporated. The residueobtained is diluted in 10 ml of ethyl acetate and 3.3 ml of 3.6Nethereal hydrogen chloride are added to yield allylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride.

Yield: 53%.

Melting point: 233°-235° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory       Found                                                    ______________________________________                                        C %       65.04          64.84  64.90                                         H %       7.76           7.66   7.87                                          N %       7.98           7.98   7.86                                          Cl %      10.10          10.05  9.88                                          ______________________________________                                    

EXAMPLE 26N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylacrylamidehydrochloride

This compound was obtained in accordance with the process described inStage F of Example 25 but replacing allyl chloroformate with acryloylchloride.

Yield: 24%.

Melting point: 230°-232° C.

    ______________________________________                                        Elemental analysis:                                                                         Theory                                                                              Found                                                     ______________________________________                                        C %             67.38   67.04                                                 H %             7.85    7.80                                                  N %             8.73    8.66                                                  Cl %            11.05   11.14                                                 ______________________________________                                    

EXAMPLE 27 N-{1-[(1,2-dihydro-1-(2-fluorophenyl)-2-oxo-1,8-naphthyridin-3-yl)-methyl]-piperid-4 yl}-N-methylpropionamideStage A 2-[(2-fluorophenyl)-amino[-nicotinic acid

50 g of 2-chloronicotinic acid and 31 ml of 2-fluoroaniline in 180 ml ofxylene are refluxed for 5 hours. The precipitate is filtered off andwashed with xylene and then with water to yield the desired compound.

Melting point: 114° C.

Proton nuclear magnetic resonance spectrum (solvent DMSO-d₆): 10.65 ppm,1 H exchangeable; 8.1 to 8.6 ppm, 3 H m+1 H exchangeable; 6.8 to 7.4ppm, 5 H, m.

Stage B 2-(2-fluorophenyl)-amino-3-hydroxymethylpyridine

59.3 g of the compound obtained in the above Stage are dissolved hot intetrahydrofuran and the solution is poured into 19.5 g of lithiumaluminum hydride suspended in tetrahydrofuran. After hydrolysis, themixture is filtered, then concentrated and purified on a silica column,using methylene chloride as eluant, to yield the desired compound.

Yield: 25%.

Melting point: 96%.

Stage C 2-[(2-fluorophenyl)-amino[-3-formylpyridine

13.5 g of the compound obtained in Stage B are dissolved in 200 ml ofmethylene chloride and then 65 g of manganous oxide are added. Themixture is stirred at room temperature for 48 hours. A further 10 g ofmanganous oxide is added and the mixture is left for 24 hours and thenfiltered, the residue is washed several times with methylene chloride,and the filtrate and washings are concentrated and purified on a silicacolumn to yield the desired compound.

Yield: 43%.

Melting point: 94° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 10.6 ppm, 1H exchangeable; 9.95 ppm, 1 H, s; 8.85 ppm, 1 H, t; 8.45 ppm, 1 H, d;7.9 ppm, 1 H, d; 7.2 to 7.0 ppm, 3 H, m; 6.9 ppm, 1 H, dd.

Stage D N-[1-(ethoxycarbonylethyl)-piperid-4-yl[-N-methylpropionamide

7.4 g of the compound obtained in Stage C of Example 1 are dissolved in10 ml of ethanol, then 4.73 ml of ethyl acrylate dissolved in 12 ml ofethanol are poured onto the solution. The mixture is left at roomtemperature for one night, and then concentrated in a rotary evaporatorand distilled in a Kugelrohr to yield the compound in the form of anoil.

Yield: 88%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 4.5 and 3.6ppm, 1 H, 2 m; 4.2 ppm, 2 H, g; 3 ppm, 2 H, m; 2.85 ppm, 3 H, 2 s; 2.7ppm, 2 H, t; 2.5 ppm, 2 H, t; 2.35 ppm, 2 H, 2 g; 2.1 ppm, 2 H, m; 2 to1.5 ppm, 4 H, m; 1.25 ppm, 3 H, t; 1.15 ppm, 3 H, 2 t.

Stage E

2.2 g of the compound obtained in Stage C and 2.8 g of the compoundobtained in stage D dissolved in 15 ml of benzene are poured onto 0.4 gof sodium hydride covered with 15 ml of benzene and the reaction isprimed with a few drops of ethanol. The reaction mixture is stirred atroom temperature for 2 days and hydrolysed with 50 ml of water. Theprecipitate is filtered off and recrystallised from 16 ml of ethanol toyieldN-{1-[1,2-dihydro-1-(2-fluorophenyl)-2-oxo-1,8-naphthyridin-3-ylmethyl]-piperid-4-yl}-N-methylpropionamide.

Yield: 16%.

Melting point: 218°-220° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory       Found                                                     ______________________________________                                        C %      68.23          68.55  68.27                                          H %      6.44           6.58   6.57                                           N %      13.26          13.24  13.18                                          ______________________________________                                    

EXAMPLE 28 EthylN-{1-[(3,4-methylenedioxybenzocyclobuten-1-yl)methyl[-piperid-4-yl}-N-methylcarbamatefumarate Stage A 2-cyano-3-(2,3-methylenedioxyphenyl)-propen-2-oic acid

160 g of 2,3-methylenedioxybenzaldehyde, 90.52 g of cyanoacetic acid,149.2 ml of pyridine and 13.6 g of ammonium acetate are mixed togetherand refluxed for 12 hours in 944 ml of toluene.

Using a Dean-Stark apparatus, 17 ml of water are removed and then themixture is left at room temperature for one night. The precipitate isfiltered off, taken up in 600 ml of 18% hydrochloric acid, the mixtureis filtered and the filtrate is washed with water until neutral.

The organic phase is extracted with a saturated sodium hydrogencarbonate solution. The resulting precipitate is kept and the aqueousphase is acidified and extracted with methylene chloride. The organicphase is extracted with a saturated sodium hydrogen carbonate solution.The resulting precipitate is kept and is the desired acid.

Yield: 47.5%.

Melting point: 230° C.

Proton nuclear magnetic resonance spectrum (solvent DMSO-d₆): 8.2 ppm, 1H, s; 7.7 ppm, 1 H, d; 7.15 ppm, 1 H, d; 7.0 ppm, 1 H, t; 6.2 ppm, 2 H,s; 3.5 ppm, 1 H exchangeable.

Stage B 2-cyano-3-(2,3-methylenedioxyphenyl)propanoic acid

60.2 g of sodium borohydride are added to a mixture containing 110 g ofthe acid obtained in Stage A and 404.5 ml of a saturated sodium hydrogencarbonate solution at 18° C. The mixture is left for 48 hours, taken upin water, washed with diethyl ether and then acidified to pH 2 withhydrochloric acid. The mixture is extracted with methylene chloride,then the organic phase is washed with water until neutral and dried toobtained the desired compound.

Yield: 55%.

Melting point: 118° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃ +DMSO-d₆): 8.8ppm, 1 H exchangeable; 6.8 ppm, 3 H, m; 6.0 ppm, 2 H, m; 3.85 ppm, 1 H,dd; 3.3 ppm, 1 H, dd; 3.10 ppm, 1 H, dd.

Stage C 2-cyano-1-(2,3methylenedioxyphenyl)-ethane

60.6 g of acid prepared in Stage B are mixed with 115 ml ofN,N-dimethylacetamide and the mixture is heated at 150° C. forapproximately 2 hours and then allowed to cool, taken up in water andextracted with diethyl ether. The ethereal phases are washed with asodium hydrogen carbonate solution and then with water and dried toyield the desired compound in the form of an oil.

Yield: 87%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 6.9 to 6.65ppm, 3 H, m; 5.95 ppm, 2 H, s; 2.95 ppm, 2 H, t; 2.65 ppm, 2 H, t.

Stage D 1-(6-bromo-2,3-methylenedioxyphenyl)-2-cyanoethane

16.4 ml of bromine dissolved in 35 ml of acetic acid are poured at 18°C. onto 53.6 g of nitrile obtained in Stage C dissolved in 179 ml ofacetic acid. The mixture is stirred for 1 hour, then left overnight atroom temperature and hydrolysed with 31.5 g of potassium acetatedissolved in 150 ml of water and 196.5 g of ice. The mixture isextracted with diethyl ether and the ethereal phase is washed severaltimes with water and dried.

Yield: 24%.

Melting point: 60°-65° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.0 ppm, 1H, d; 6.65 ppm, 1 H, d; 6.0 ppm, 2 H, s; 3.05 ppm, 2 H, t; 2.65 ppm, 2H, t.

Stage E 1-cyano--3,4-methylenedioxybenzocyclobutene

15 g of the compound obtained in the above Stage are added to 0.1 mol ofsodium amide in liquid ammonia. The mixture is left for 15 minutes andthen neutralised with 10.2 g of ammonium chloride. The ammonia isallowed to evaporate and then the residue is taken up in water anddiethyl ether. The insoluble material is filtered off, the filtrate isdecanted and the aqueous phase is re-extracted with diethyl ether. Theorganic phases are combined, washed with N hydrochloric acid and thendried over magnesium sulphate.

Yield: 57%.

Melting point: 80° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 6.6 to 6.9ppm, 2 H, d; 5.95 ppm, 2 H, s; 4.2 ppm, 1 H, m; 3.55 ppm, 2 H, m.

Stage F 3,4-methylenedioxybenzocyclobuten-1-ylcarboxylic acid

5.8 g of the compound prepared above are stirred at room temperature forone night in an ethanolic solution of potassium hydroxide (6.7 g in 48ml of ethanol). 9 ml of water are then added and the mixture is refluxedfor 4 hours, concentrated, taken up in water, washed several times withdiethyl ether, acidified to pH 1 with concentrated hydrochloric acid andthen extracted with diethyl ether and dried.

Yield: 99%.

Melting point: 125° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 6.7 ppm, 2H, 2 d; 5.95 ppm, 2 H, s; 4.3 ppm, 1 H, t; 3.45 ppm, 2 H, d.

Stage G 1-hydroxymethyl-3,4-methylenedioxybenzocyclobutene

Under a nitrogen atmosphere, 7.4 g of lithium aluminium hydride areadded to 100 ml of diethyl ether and then 15 g of the compound preparedin Stage F, dissolved in 300 ml of diethyl ether, are added dropwisethereto. When the addition is complete, the mixture is refluxed for 3hours. The excess hydride is hydrolysed, the mixture is filtered, theresidue is washed several times with diethyl ether and the filtrate andwashings are concentrated. The alcohol is obtained in the form of anoil.

Yield: 87%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 6.65 ppm, 2H, 2 d; 5.9 ppm, 2 H, s; 3.9 ppm, 2 H, m; 3.65 ppm, 1 H, m; 3.25 ppm, 1H, dd; 2.9 ppm, 1 H, dd; 1.5 ppm, 1 H exchangeable.

Stage H 1-methyl-3,4-methylenedioxybenzocyclobutene tosylate

19 g of para-toluenesulphonyl chloride are added at 0° C. to 12.1 g ofthe alcohol obtained in the above Stage dissolved in 84 ml of pyridine.The mixture is stirred for 48 hours at room temperature, concentrated,taken up in water and filtered, and the residue is washed several timeswith water and then with 1 N hydrochloric acid and dried.

Yield: 82%.

Melting point: 102° C.

Proton nuclear magnetic resonance spectrum (solvent DMSO-d₆): 7.75 ppm,2 H, d; 7.45 ppm, 2 H, d; 6.75 ppm, 1 H, d; 6.55 ppm, 1 H, d; 5.95 ppm,2 H, s; 4.25 ppm, 2 H, m; 3.7 ppm, 1 H, m; 3.3 to 3.1 ppm, 1 H, 2 d; 2.7to 2.8 ppm, 1 H, 2 d; 2.4 ppm, 3 H, s.

Stage I

4 g of the compound obtained in Stage H, 2.24 g of the compound obtainedin Stage B of Example 6 and 1.7 ml of triethanolamine are refluxed in 40ml of toluene for 24 hours. The reaction mixture is concentrated, takenup in ethyl acetate, washed with water and then extracted with 1 Nhydrochloric acid, and the extract is rendered basic with concentratedsodium hydroxide solution and extracted with methylene chloride. Theextract is dried to yield ethylN-{1-[(3,4-methylenedioxybenzocyclobuten-1-yl)-methyl]-piperid-4-yl)-N-methylcarbamate.23.5 ml of a 2% solution of fumaric acid in ethanol are added to yieldthe desired salt.

Yield: 17%.

Melting point: 138°-142° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            59.73   59.45                                                  H %            6.54    6.41                                                   N %            6.06    5.82                                                   ______________________________________                                    

EXAMPLE 29N-{[1-(3,4-methylenedioxybenzocyclobuten-1-yl)-methyl]piperid-4-yl}-N-methylpropionamidehydrochloride

This compound was prepared in accordance with the process described inStage I of Example 28 but using N-piperid-4-yl-N-methylpropionamideinstead of methyl N-piperid-4-yl-N-methylcarbamate. Ethereal hydrogenchloride was used for the salt formation.

Yield: 36%.

Melting point: 208°-211° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory       Found                                                    ______________________________________                                        C %       62.20          62.10  61.83                                         H %       7.42           7.58   7.46                                          N %       7.64           7.51   7.39                                          Cl %      9.66           9.39   9.36                                          ______________________________________                                    

EXAMPLE 30N-{1-[(1,2dihydro-2-oxo-1-phenyl-1,8-naphthyridin-3-yl)methyl]-piperid-4-yl}-N-methylpropionamide

This compound was prepared in accordance with the process described inExample 27 but using aniline instead of 2-fluoroaniline in Stage A.

Yield: 16.5%.

Melting point: 181°-183√ C.

    ______________________________________                                        Elemental analysis:                                                                  Theory       Found                                                     ______________________________________                                        C %      71.26          71.57  71.53                                          H %      6.98           7.25   7.26                                           N %      13.85          14.12  14.25                                          ______________________________________                                    

EXAMPLE 31 N-(1-indan-2-ylpiperid-4-yl)-N-methylpropionamide State AIndanyl p-toluenesulphonate

47.4 g of tosyl chloride are added to 30 g of 2-indanol dissolved in 75ml of pyridine which has been cooled to 0° C. The mixture is left atthat temperature for 3 hours and then at room temperature for one night.The reaction solution is then poured onto 450 ml of 2.6 N hydrochloricacid, filtered, and the residue washed with water to yield the desiredcompound.

Melting point: 117° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.8 ppm, 2H, d; 7.35 ppm, 2 H, d; 7.15 ppm, 4 H, s; 5.3 ppm, 1 H, m; 2.95 to 3.35ppm, 4 H, m; 2.5 ppm, 3 H, s.

Stage B

4 g of the compound obtained in the above Stage, 2.95 g of the compounddescribed in Stage C of Example 1, and 3 ml of N,N-diisopropylethylaminein 40 ml of toluene are mixed together and refluxed for 24 hours.

The reaction mixture is concentrated and taken up in diethyl ether,washed with water and extracted with hydrochloric acid.

The aqueous phase is rendered basic and extracted with diethyl ether.The extract is dried, concentrated and recrystallised from 7 ml of ethylacetate.

Yield: 30%.

Melting point 126°-129° C.

    ______________________________________                                        Elemental analysis:                                                                  Theory       Found                                                     ______________________________________                                        C %      75.48          75.76  75.19                                          H %      9.15           8.96   9.19                                           N %      9.78           9.80   9.70                                           ______________________________________                                    

EXAMPLE 32 EthylN-{1-[[1,2-dihydro-2-oxo-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-3-yl[-ethyl[-piperid-4-yl}-N-methylcarbamatehydrochloride Stage A1,2-dihydro-3-hydroxyethyl-2-oxo-1-(3-trifluoromethylphenyl)-1,8-naphthyridine

7.2 g of 60% sodium hydride are covered with 150 ml of benzene, then31.5 g of 2-[(3-trifluorophenyl)-amino]-3-formylpyridine (prepared inaccordance with the process described in Stages A-C of Example 27) and31.25 g of γ-butyrolactone dissolved in 150 ml of benzene are addeddropwise. The reaction is primed with a few drops of ethanol. Thereaction mixture is left at room temperature for one night, hydrolysedwith 50 ml of water and then the benzene is decanted off. The organicphase is washed with water. The aqueous phases are re-extracted withmethylene chloride and the organic phases are combined and dried.

Yield: 50%.

Melting point: 175° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 8.4 ppm, 1H, dd; 7.95 ppm, 1 H, dd; 7.8 to 7.65 ppm, 3 H, m; 7.6 ppm, 1 H, sbroad; 7.5 ppm, 1 H, dd; 7.2 ppm, 1 H, dd; 3.95 ppm, 2 H, d; 2.95 ppm, 2H, t; 2.7 ppm, 1 H, t.

Stage B3-chloroethyl-1,2-dihydro-2-oxo-1-(3-trifluoromethylphenyl)-1,8-naphthyridine

19.5 g of the alcohol prepared above are dissolved in 244 ml ofmethylene chloride. 13 ml of thionyl chloride are added dropwisethereto. The reaction mixture is refluxed for 3 hours and allowed tocool, then the methylene chloride is washed with water, then with 0.1 Nsodium hydroxide, dried and then the product is recrystallised fromdiisopropyl ether.

Yield: 78%.

Melting point: 124° C.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 8.3 ppm, 1H, dd; 7.9 ppm, 1 H, dd; 7.65 ppm, 1 H, s; 7.7 to 7.3 ppm, 4 H, m; 7.1ppm, 1 H, m; 3.8 ppm, 2 H, t; 3.05 ppm, 2 H, t.

Stage C

3.5 g of the compound obtained in the above Stage, 1.85 g of thecompound obtained in Stage B of Example 6 and 3.15 g of sodium carbonateare mixed in 60 ml of methyl isobutyl ketone and refluxed for 7 hours.

The reaction mixture is concentrated, taken up with water and withdiethyl ether, and extracted with N hydrochloric acid. The extract isrendered basic with sodium hydroxide solution, concentrated andextracted with diethyl ether.

The oily base so obtained is dried and converted into a salt using 3.2 Nethereal hydrogen chloride.

The hydrochloride is concentrated and recrystallised from ethyl acetateand then from ethanol.

Yield: 10%.

Melting point: 220°-225° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory       Found                                                    ______________________________________                                        C %       57.94          57.79  57.40                                         H %       5.61           5.68   5.70                                          N %       10.39          10.26  10.32                                         Cl %      6.58           6.57   6.50                                          ______________________________________                                    

EXAMPLE 33N-{1-[[1,2-dihydro-2-oxo-1-(3-trifluoromethylphenyl)-1,8-naphthyridin-3-yl]-ethyl]-piperid-4-yl}-N-methylpropionamidehydrochloride

This compound was prepared in accordance with the process described inExample 32 but replacing ethyl N-piperid-4-yl-N-methylcarbamate withN-piperid-4-yl-N-methylpropionamide in Stage C.

Yield: 10%.

Melting point: 271°-274° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory      Found                                                     ______________________________________                                        C %       59.71         59.93  59.51                                          H %       5.78          5.75   5.90                                           N %       10.71         10.64  10.51                                          Cl %      6.78          6.71   6.81                                           ______________________________________                                    

EXAMPLE 34N-{1-[(2,3-dihydrobenzofuran-2-yl)-methyl]-piperid-4-yl}-N-methylpropionamidehydrochloride

5.1 g of N-piperid-4-N-methylpropionamide acetate, 90 m ofdimethylformamide and 6.3 ml of triethylamine are introduced into a 250ml three-necked flask. 6.6 g of 2,3-dihydro-2-iodomethylbenzofuran arepoured onto the mixture which is heated to 60°-65° C. This temperatureis maintained for 15 hours. The reaction mixture is evaporated todryness and the residue is taken up in ethyl acetate and extracted with150 ml of N hydrochloric acid. The aqueous phase is rendered alkalinewith sodium hydroxide in the presence of ethyl acetate. The organicphase is washed with water and dried over magnesium sulphate. Thesolvent is evaporated to yield a base in the form of a brown oil, whichis converted into a salt with 3.8 N ethereal hydrogen chloride to yieldthe desired compound.

Yield: 30%.

Melting point: 153°-156° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            63.80   63.38                                                  H %            8.03    8.03                                                   N %            8.27    8.17                                                   Cl %           10.46   10.06                                                  ______________________________________                                    

EXAMPLE 35N-{1-(benzocyclobuten-1ylethyl)-piperid-4-yl}-N-methylpropionamidehydrochloride

This compound was prepared from 1-bromoethylbenzocyclobutene andN-piperid-4-yl-N-methylpropionamide in accordance with the processdescribed in Example 29.

Yield: 55%.

Melting point: 240°-230° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            67.74   67.59                                                  H %            8.68    8.66                                                   N %            8.31    8.13                                                   Cl %           10.52   10.45                                                  ______________________________________                                    

EXAMPLE 361-[(1-benzocyclobuten-1-ylmethyl)-piperid-4-yl]-1-methyl-3-phenylureahydrochloride

0.02 mol of phenyl isocyanate dissolved in 20 ml of diethyl ether isadded to a solution of 1-benzocyclobuten-1-yl-4-methylaminopiperidine indiethyl ether while maintaining the temperature between 0° and 5° C. Thereaction mixture is left at that temperature for 1 hour and then theresulting precipitate is filtered off to yield the desired urea. Thiscompound is then dissolved in acetonitrile and converted into a saltwith an appropriate amount of ethereal hydrogen chloride.

Yield: 80%.

Melting point: >260° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory      Found                                                     ______________________________________                                        C %       68.47         68.38  68.08                                          H %       7.31          7.31   7.26                                           N %       10.89         11.06  11.10                                          Cl %      9.19          8.79   8.58                                           ______________________________________                                    

EXAMPLE 371-[(1-benzocyclobuten-1-ylmethyl)-piperid-4-yl]-3-ethyl-1methylureahydrochloride

This compound was prepared in accordance with the process described inExample 36 but replacing phenyl isocyanate with ethyl isocyanate.

Yield: 65%.

Melting point: >260° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory      Found                                                     ______________________________________                                        C %       63.98         63.99  63.63                                          H %       8.35          8.40   8.36                                           N %       12.44         12.57  12.67                                          Cl %      10.49         10.47  10.23                                          ______________________________________                                    

EXAMPLE 381-[(1-benzocyclobuten-1-ylmethyl)-piperid-4-yl]-3-benzyl-1-methylurea

This compound was prepared in accordance with the process described inExample 36 but replacing phenyl isocyanate with benzyl isocyanate.

Yield: 85%.

Melting point: 148°-150° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory      Found                                                     ______________________________________                                        C %       76.00         75.56  75.92                                          H %       8.04          8.01   7.99                                           N %       11.56         11.55  11.69                                          ______________________________________                                    

EXAMPLE 39N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylmethacrylamidehydrochloride

2.08 g of methacryloyl chloride are poured slowly, at room temperature,onto 4.6 g of 1-[(4-methylaminopiperid-1yl)-methyl]-benzocyclobutene(prepared in State E of Example 25) and 2.02 g of triethylamine in 50 mlof benzene.

The reaction mixture is left at room temperature for one night and thentransferred to a dropping funnel and extracted with a normal HClsolution. The combined aqueous phases are rendered basic in the cold andthen extracted with ether.

Flash chromatography (CH₃ COOC₂ H₅) yields 1.6 g ofN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylmethacrylamidein the form of an oil.

Yield: 26%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 to 7ppm, 4 H, m; 5.15 to 5 ppm, 2 H, 2 m; 4.5 and 3.7 ppm, 1 H, 2 m; 3.7ppm, 1 H, m; 3.4 ppm, 1 H, dd; 3.1 ppm, 2 H, d; 2.9 to 2.7 ppm, 2 H,dd+m; 2.6 ppm, 1 H, dd; 2.2 ppm, 2 H, m; 2 ppm, 3 H, s; 2 to 1.5 ppm, 4H, m.

The hydrochloride ofN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylmethacrylamidewas obtained by adding the stoichiometric amount of 3.6 N etherealhydrogen chloride to 1.6 g of the base prepared above dissolved in 10 mlof acetonitrile. 0.6 g of the desired compound is obtained afterfiltration and recrystallisation from methanol.

Yield: 34%.

Melting point: >260° C. (K).

    ______________________________________                                        Elemental analysis:                                                                   Theory      Found                                                     ______________________________________                                        C %       68.14         67.90  67.91                                          H %       8.13          8.06   8.12                                           N %       8.36          7.92   8.03                                           Cl %      10.59         10.87  10.53                                          ______________________________________                                    

EXAMPLE 40 N-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylformamide

11 ml of acetic anhydride are added dropwise to a solution of 32 ml of88% formic acid and 3 g of1-[(4-methylaminopiperid-1-yl)-methyl]-benzocyclobutene (cf. Stage E ofExample 25) that has been preheated to 40° C.

The reaction mixture is stirred for one night, and then evaporated,taken up in iced water, rendered basic in the cold and extracted withether. Evaporation and recrystallisation from 15 ml of diisopropyl etheryield 5.3 g ofN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylformamide.

Yield: 48%.

Melting point: 86°-88° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory      Found                                                     ______________________________________                                        C %       74.38         74.21  74.34                                          H %       8.58          8.57   8.63                                           N %       10.84         10.79  10.68                                          ______________________________________                                    

EXAMPLE 41 (R,S)-2-oxapropylN-[1-(benzocyclobuten-1-ylmethyl)piperid-4--yl]-N-methylcarbamatehydrochloride Stage A

Proceeding as described in Stage B of Example 1 starting from1-benzyl-4-methylaminopiperidine (described in Stage A of Example 1) and##STR24## 2-oxapropyl N-(1-benzylpiperid-4-yl)-N-methylcarbamate isobtained.

Yield: 87%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.3 ppm, 5H, m; 4.5 and 3.5 ppm, 1 H, 2 m; 4.10 and 4 ppm, 2 H, 2 s; 3.5 ppm, 2 H,m; 3.4 ppm, 3 H, s; 3 ppm, 2 H, m; 2.8 ppm, 3 H, s; 2.35 to 1.5 ppm, 6H, m.

Stage B

22 g of the base obtained above in 220 ml of ethanol and 4.8 ml ofacetic acid are hydrogenated under a pressure of 5 kg of hydrogen at 50°C. in the presence of 2.2 g of palladium hydroxide. The catalyst is thenfiltered off, the solution is evaporated and the residue is taken up in500 ml of methylene chloride and rendered basic in the cold with 60 mlof 20% sodium hydroxide solution. Decanting, drying and evaporationyield 9.3 g of 2-oxapropyl N-(piperid-4-yl)-N-methylcarbamate in theform of an oil.

Yield: 62%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 4.55 to 3.6ppm, 1 H, 2 m; 4.1 ppm, 2 H, 2 s; 2.45 ppm, 3 H, 2 s; 3.2 ppm, 2 H, m;2.85 ppm, 3 H, 2 s; 2.75 ppm, 2 H, m; 1.9 to 1.55 ppm, 4 H, m; 3.8 ppm,1 H exchanged with D₂ O, s.

Stage C

1.8 g of 2-oxapropyl N-(piperid-4-yl)N-methylcarbamate obtained above,1.1 g of triethylamine and 2.8 g of 1-hydroxymethylbenzocyclobutanetosylate in 50 ml of toluene are refluxed for one night with stirring.

The reaction mixture is evaporated, taken up in ether and extracted witha normal HCl solution.

The aqueous phases are rendered basic in the cold and extracted withethyl acetate to yield 1.6 g of 2-oxapropylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamate.

Yield: 14%.

Proton nuclear magnetic resonance spectrum (solvent CDCl₃): 7.25 to 7ppm, 4 H, m; 4.6 to 4.4 and 3.7 to 3.5 ppm, 1 H, m; 4.1 ppm, 2 H, s; 3.7ppm, 1 H, m; 3.5 to 3.2 ppm, 4 H, s+m; 3 to 1.5 ppm, 12 H, s+5 m; 3.1ppm, 2 H, m.

Stage D

2-oxapropylN-[1-(benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride is obtained by adding the stoichiometric amount of 3 N HClin ether to 1.4 g of the base prepared in Stage C in 5 ml ofacetonitrile.

After filtration and drying 1 g of the desired hydrochloride isobtained.

Yield: 77%.

Melting point: 204°-206° C. (K).

    ______________________________________                                        Elemental analysis:                                                                    Theory                                                                              Found                                                          ______________________________________                                        C %        63.80   63.52         corrected                                    H %        8.03    7.87          for 0.7%                                     N %        8.27    8.18          H.sub.2 O                                    Cl %       10.46   10.38                                                      ______________________________________                                    

EXAMPLE 42 (R,S)-vinylN-[1-(benzocyclobuten-1ylmethyl)-piperid-4-yl]-N-methylcarbamatehydrochloride

Proceeding as described in Example 39 starting from 3 g of1-[(4-methylaminopiperid-1-yl)-methyl]-benzocyclobutene (prepared inStage E of Example 25) and vinyl chloroformate, (R,S)-vinylN-[1-benzocyclobuten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamate isobtained, which is dissolved in 5 ml of acetonitrile and converted intoa salt with a 3.6 N HCl solution in ether to yield 1.3 g of (R,S)-vinylN-[1-(benzocyclobuten-1-ylmethyl)piperid-4-yl]-N-methylcarbamatehydrochloride.

Yield: 30%.

Melting point: 232°-234° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory      Found                                                     ______________________________________                                        C %       64.18         63.89  63.80                                          H %       7.48          7.34   7.77                                           N %       8.32          8.29   8.17                                           Cl %      10.52         10.82  10.64                                          ______________________________________                                    

EXAMPLE 43 Isobutyl N-[1-(indan-2-yl)-piperid-4-yl]-N-methylcarbamatefumarate

A mixture of 3.71 g of isobutyl N-(piperid-4-yl)-N-methylcarbamate(prepared in Example 15), 4.9 ml of triethylamine, 50 ml of toluene and5 g of indan-2-yl p-toluenesulphonate (prepared in accordance with StageA of Example 31) is refluxed for 24 hours.

The precipitate is filtered off and washed several times with toluene.The washings and filtrate are then washed several times with water,dried and concentrated. The resulting oil is taken up in a 2% solutionof fumaric acid in ethanol (mol per mol). Concentration andrecrystallisation from 10 ml of ethanol yield isobutylN-[1-(indan-2-yl)-piperid-4-yl]-N-methylcarbamate fumarate.

Yield: 14%.

Melting point: 230°-234° C. with sublimation towards 180°-185° C.

    ______________________________________                                        Elemental analysis:                                                                   Theory      Found                                                     ______________________________________                                        C %       64.55         64.79  64.67                                          H %       7.67          7.71   7.62                                           N %       6.27          6.11   6.18                                           ______________________________________                                    

EXAMPLE 44 Propyl N-[1-(indan-2-yl)-piperid-4-yl]-N-methylcarbamate

A mixture of 3.47 g of propyl N-(piperid-4-yl)-N-methylcarbamate(prepared in Example 9), 4.9 ml of triethylamine, 50 ml of toluene and 5g of indan-2-yl p-toluenesulphonate (prepared according to Stage A ofExample 31) is refluxed for 24 hours.

100 ml of water are then added to this reaction mixture and, afterdecanting, the organic phase is extracted with a normal HCl solution.The acidic aqueous phase is then rendered basic with a normal sodiumhydroxide solution and subsequently extracted with CH₂ Cl₂ and driedover MgSO₄. The resulting solid is recrystallised from 10 ml ofdiisopropyl ether.

Yield: 42%.

Melting point: 73°-76° C.

    ______________________________________                                        Elemental analysis:                                                                        Theory                                                                              Found                                                      ______________________________________                                        C %            72.12   71.76                                                  H %            8.92    8.79                                                   N %            8.85    9.04                                                   ______________________________________                                    

                                      TABLE I                                     __________________________________________________________________________    COMPOUNDS OF THE GENERAL FORMULA I                                             ##STR25##                                                   (I)              EX-                                                                           AM-                                                                           PLE                                                                              R             m K       p L              NMR Spectrum                      __________________________________________________________________________                                                (solvent)                          1                                                                                ##STR26##    1                                                                                ##STR27##                                                                            0                                                                                ##STR28##     .sup.1 H NMR (CDCl.sub.3)                                                     salt 8.1 ppm, 1H, dd; 7.5 to                                                  7.7 ppm, 2H, m; 7.4 ppm, 1H,                                                  m; 6.7 ppm, 1H, s; 4.8 ppm,                                                   1H, m; 4.3 ppm, 2H, s; 3.7                                                    ppm, 2H, d; 3.2 ppm, 2H, t;                                                   2.9 ppm, 3H, s; 2.5 to 2.9                                                    ppm, 2H, m; 2.3 ppm, 2H, q;                                                   1.8 ppm, 2H, m; 1.1 ppm, 3H,                                                  t; 13.15 ppm, 1H                                                              exchangeable.                      2                                                                                ##STR29##    1                                                                                ##STR30##                                                                            0                                                                                ##STR31##     .sup.1 H NMR (CDCl.sub.3)                                                     base 8.2 ppm, 1H, dd; 7.7                                                     ppm, 1H, td; 7.45 ppm, 2H, m;                                                 6.5-6.45, 1H, 2s; 4.55-3.6                                                    ppm, 1H, 2m; 3.55-3.5, 2H,                                                    2s; 3.1 ppm, 2H, m; 2.9 to                                                    2.85 ppm, 3H, 2s; 2.3 ppm,                                                    4H, m 1.5 to 1.85 ppm, 6H, m;                                                 1 ppm, 3H, t                       3                                                                                ##STR32##    1                                                                                ##STR33##                                                                            0                                                                                ##STR34##     .sup.1 H NMR (CDCl.sub.3)                                                     base 8.2 ppm, 1H, dd; 7.7                                                     ppm, 1H, td; 7.45 ppm, 2H, m;                                                 6.45 ppm, 1H, 2s; 4.5+3.6                                                     ppm, 1H, 2m; 3.55 ppm, 2H,                                                    2s; 3.1 ppm, 2H, m; 2.9 to                                                    2.85 ppm, 3H, 2s; 2.35 ppm;                                                   2H, m 2.1 ppm, 3H, 2s; 2.1 to                                                 .5 ppm, 4H, m                      4                                                                                ##STR35##    1                                                                                ##STR36##                                                                            0                                                                                ##STR37##     .sup.1 H NMR (CDCl.sub.3)                                                     salt 8.05 ppm, 1H, d; 7.95                                                    ppm, 1H, t; 7.70 ppm 1H, d;                                                   7.55 ppm, 1H, t; 6.7 ppm, 1H,                                                 2s; 4.4 ppm, 2H, s; 4.4 to 4                                                  ppm, 1H, 2m; 3.6 ppm, 2H, m;                                                  3.25 ppm, 4H, m; 2.35 ppm,                                                    4H, m; 1.8 ppm, 2H, m; 1.15                                                   to 1.05 ppm, 6H, 1+2t; 11.75                                                  ppm, 1H exchangeable               5                                                                                ##STR38##    2                                                                                ##STR39##                                                                            0                                                                                ##STR40##     .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 8.05 ppm, 1H, 2d; 7.8                                                    ppm, 1H, t; 7.6 ppm 1H, d;                                                    7.5 ppm, 1H, t; 6.4 ppm, 1H,                                                  s; 4.6+4 ppm, 1H, 2m; 3.55                                                    ppm, 4H, m; 3.2 ppm, 4H, m;                                                   2.8+2.6 ppm, 3H, 2s; 2.4+2.3                                                  ppm, 2H, 2q; 2.10 ppm, 2H, m;                                                 .7 ppm, 2H, m; 1 ppm, 3H, 2t;                                                 11.2 ppm, 1H exchangeable          6                                                                                ##STR41##    1                                                                                ##STR42##                                                                            0                                                                                ##STR43##     .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 8.05 ppm, 1H, dd; 7.85                                                   ppm, 1H, td; 7.7 ppm, 1H, d;                                                  7.55 ppm, 1H, t; 6.75 ppm,                                                    1H, s; 4.4 ppm, 2H, s; 4.15                                                   ppm, 1H, m; 4.05 ppm, 2H, q;                                                  3.6 ppm, 2H, m; 3.3 ppm, 2H,                                                  m; 2.75 ppm, 3H, s; 2.3 ppm,                                                  2H, m; 1.75 ppm, 2H, m; 1.2                                                   ppm, 3H, t; 11.7 ppm, 1H                                                      exchangeable                       7                                                                                ##STR44##    1                                                                                ##STR45##                                                                            0                                                                                ##STR46##     .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 8.05 ppm, 1H, d; 7.9                                                     ppm, 1H, t; 7.7 ppm 1H, d;                                                    7.55 ppm, 1H, t; 6.75 ppm,                                                    1H, 2s; 4.6+4.1 ppm, 1H, 2m;                                                  4.4 ppm, 2H, s; 3.6 ppm, 2H,                                                  m; 3.3 ppm, 2H, m; 2.9+2.7                                                    ppm 3H, 2s, 2.85 ppm, 1H, s;                                                  2.35 ppm, 2H, m; 1.7 ppm, 2H,                                                 m; 1 ppm, 6H, d; 12-11.5 ppm,                                                 1H exchangeable                    8                                                                                ##STR47##    1                                                                                ##STR48##                                                                            0                                                                                ##STR49##     .sup.1 H NMR (CDCl.sub.3)                                                     base 7.3 to 7 ppm, 4H, m; 4.4                                                 ppm, 1H, m; 4.2 ppm, 1H, m;                                                   3.8 to 3.4 ppm, 6H, m; 3.3 to                                                 3.0 ppm, 2H, m; 3 to 2.6 ppm,                                                 8H, m; 1.85 ppm, 2H, m; 13 to                                                 12.7 ppm, 1H exchangeable          9                                                                                ##STR50##    1                                                                                ##STR51##                                                                            0                                                                                ##STR52##     .sup.1 H NMR (CDCl.sub.3)                                                     salt 7.4 to 7 ppm, 4H, m; 4.4                                                 ppm, 1H, m; 4.3 to 3.9 ppm,                                                   3H, m+t; 3.9 to 3.3 ppm, 3H,                                                  m+m; 3.3 to 3 ppm, 2H, m+m;                                                   2.85 ppm 3H, s; 3 to 2.5 ppm,                                                 3H, m+m; 2 to 1.5 ppm, 6H,                                                    m+m+m; 0.95 ppm, 3H, t; 12.75                                                 ppm, 1H exchangeable              10                                                                                ##STR53##    1                                                                                ##STR54##                                                                            0                                                                                ##STR55##     .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 7.3 to 7 ppm, 4H, m; 4.5                                                 et 4.2 ppm, 1H, 2m; 3.9 ppm,                                                  1H, m; 3.5 ppm, 1H, m; 3.5 to                                                 3 ppm, 7H, 4m; 2.8 and 3 ppm                                                  3H, 2s; 2.1 to 2.6 ppm, 2H,                                                   m; 1.85 ppm, 2H, m; 10.75                                                     ppm, 1H echangeable               11                                                                                ##STR56##    1                                                                                ##STR57##                                                                            0                                                                                ##STR58##     .sup.1 H NMR (CDCl.sub.3 +                                                    DMSO) 7.3 to 7 ppm, 4H, m;                                                    4.50 to 4.05 ppm 2H, m; 2.8                                                   ppm, 3H, s; 1.85 ppm, 2H, d                                                   1.45 ppm, 9H, s; 3.8 to 2.4                                                   ppm, 10H, m; 13 to 12 ppm, 1H                                                 exchangeable                      12                                                                                ##STR59##    1                                                                                ##STR60##                                                                            0                                                                                ##STR61##     .sup.1 H NMR (DMSO-d.sub.6)                                                   7.5 to 7 ppm, 9H, m; 4.3 ppm,                                                 1H, m; 4 ppm, 1H, m; 3.7 to 3                                                 ppm, 8H, 4m; 2.9 ppm, 3H, m;                                                  2.5 to 2.2 ppm, 2H, m; 1.9                                                    ppm, 2H, m; 10.9 ppm, 1H                                                      exchangeable                      13                                                                                ##STR62##    1                                                                                ##STR63##                                                                            0                                                                                ##STR64##     .sup.1 H NMR (DMSO-d.sub.6)                                                   7.2 ppm, 4H, m; 4.2 to 3.3                                                    ppm, 4H, m; 3.7 to 3 ppm,                                                     10H, m; 1.8 ppm, 4H, m; 1.2                                                   ppm, 3H, t; 1.05 ppm, 3H, t;                                                  10.9 ppm, 1H exchangeable         14                                                                                ##STR65##    1                                                                                ##STR66##                                                                            0                                                                                ##STR67##     .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 7.3 to 7 ppm, 4H, m; 4.1                                                 to 3.8 ppm, 1H+1H m+m; 3.6                                                    ppm, 3H, s; 3.6 to 3 ppm,                                                     1H+1H+ 2H+4H+2H, m+m+m+m+m;                                                   2.3 ppm, 2H, m; 1.75 ppm, 2H,                                                 m, 1.1 ppm, 3H, t; 10.95 ppm,                                                 1H exchangeable                   15                                                                                ##STR68##    1                                                                                ##STR69##                                                                            0                                                                                ##STR70##     .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 7.15 ppm, 4H, m; 6.6                                                     ppm, 2H, s; 4 to 3.6 ppm, 2H,                                                 m; 3.8 ppm, 2H, d; 3.3 ppm,                                                   1H, dd; 3.15 ppm, 2H, m; 3 to                                                 2.6 ppm, 3H, m; 2.75 ppm, 3H,                                                 s; 2.3 ppm, 2H, m; 2 to 1.7                                                   ppm, 3H, m; 1.6 ppm, 2H, m;                                                   0.9 ppm, 6H, d                    16                                                                                ##STR71##    1                                                                                ##STR72##                                                                            0                                                                                ##STR73##     .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 8.15 and 8.05 ppm, 1H,                                                   2d; 7.1 to 7.3 ppm, 4H, m;                                                    4.0 ppm, 1H, m; 3.75 ppm, 1H,                                                 m 3.6 to 2.9 ppm, 8H, m; 2.3                                                  to 2.0 ppm, 2H, q; 2.1 to 1.7                                                 ppm, 4H, m; 1 ppm, 3H, 2t                                                     11.05 and 10.8 ppm 1H                                                         exchangeable                      17                                                                                ##STR74##    1                                                                                ##STR75##                                                                            0                                                                                ##STR76##     .sup.1 H NMR (CDCl.sub.3)                                                     salt 7.3 to 7, 4H, m; 4.5 to                                                  4.1 ppm, 4H, m+m+m; 3.8 to                                                    3.3 ppm, 8H, m+m+m+s+m; 3.3 a                                                 3 ppm, 3H, m 3 to 2.6 ppm, 7H                                                 s+m+m; 1.8 ppm 2H, m; 12.8                                                    ppm, 1H exchangeable              18                                                                                ##STR77##    1                                                                                ##STR78##                                                                            0                                                                                ##STR79##     .sup.1 H NMR (DMSO - d.sub.6)                                                 salt 7.2 ppm, 4H, m; 4.55                                                     ppm, 1H, m; 4.3 to 3.8 ppm,                                                   2H, m+m; 3.7 to 2.9 ppm, 8H,                                                  m+m+m+m; 2.75 ppm, 3H, s; 2.2                                                 pm, 2H, m; 1.9 to 1.2 ppm,                                                    12H, m; 10.95 ppm, 1H                                                         exchangeable                      19                                                                                ##STR80##    1                                                                                ##STR81##                                                                            0                                                                                ##STR82##     .sup.1 H NMR (DMSO - d.sub.6)                                                 salt 7.6 to 7 ppm, 9H, m; 5.1                                                 ppm, 2H, s; 4.2 ppm, 1H, m;                                                   3.95 ppm, 1H, m; 3.8 to 3                                                     ppm, 8H, m; 2.8 ppm, 3H, s;                                                   2.25 ppm, 2H, m; 1.8 ppm, 2H,                                                 d; 11.2 ppm 1H exchangeable       20                                                                                ##STR83##    1                                                                                ##STR84##                                                                            0                                                                                ##STR85##     .sup.1 H NMR (CDCl.sub.3)                                                     salt 7.4 to 7.0 ppm, 4H+1                                                     echangeable, m; 4.8 ppm, 1H,                                                  m; 3.9 to 2.6 ppm, 11H, m 2.3                                                 ppm, 2H, q; 1.8 ppm, 3H, s;                                                   1.9 to 1.5 ppm, 4H, m; 1.15                                                   ppm, 3H, t                        21                                                                                ##STR86##    1                                                                                ##STR87##                                                                            0                                                                                ##STR88##     .sup.1 H NMR (CDCl.sub.3)                                                     salt 7.25 ppm, 2H, m; 7.1                                                     ppm, 2H, m; 4.8 ppm, 1H, m;                                                   4.2 ppm, 1H, m; 3.8-3.1 ppm,                                                  8H, m; 2.9-2.7 ppm, 4H, 2m;                                                   2.15 ppm, 3H, s; 1.9 ppm, 2H,                                                 m; 1.25 ppm, 3H, t; 12.8 ppm,                                                 1H exchangeable                   22                                                                                ##STR89##    1                                                                                ##STR90##                                                                            0                                                                                ##STR91##     .sup.1 H NMR (CDCL.sub.3)                                                     salt 7.25 ppm, 2H, m; 7.1                                                     ppm, 2H, m; 4.85 ppm, 1H, m;                                                  4.2 ppm, 1H, m; 3.75 ppm,                                                     2H, m; 3.6 ppm, 1H, dd; 3.5                                                   ppm, 1H, dd; 3.25 ppm, 1H,                                                    dd; 3.15 ppm, 1H, dd; 3.0 to                                                  2.6 ppm, 4H, m; 3.0 ppm, 3H,                                                  s; 2.35 ppm, 2H, q; 1.8 ppm,                                                  2H, m; 1.15 pm, 3H, t; 12.75                                                  ppm, 1H exchangeable              23                                                                                ##STR92##    1                                                                                ##STR93##                                                                            0                                                                                ##STR94##     .sup.1 H NMR (CDCL.sub.3)                                                     salt 7.25 ppm, 2H, m; 7.1                                                     ppm, 2H, m; 4.4 ppm, 1H, m;                                                   4.15 ppm, 3H, m+q; 3.75 ppm,                                                  2H, m; 3.6 ppm, 1H, dd; 3.5                                                   ppm, 1H, dd; 3.25 ppm, 1H, d;                                                 3.1 ppm, 1H, dd; 2.85 ppm,                                                    3H, s; 3.05-2.6 ppm, 4H, m;                                                   1.85 ppm, 2H, m; 1.3 ppm, 3H,                                                 ; 11.7 ppm 1H exchangeable        24                                                                                ##STR95##    1                                                                                ##STR96##                                                                            0                                                                                ##STR97##     .sup.1 H NMR (CDCl.sub.3)                                                     salt 7.25 ppm, 2H, m; 7.1                                                     ppm, 2H, m; 4.85 ppm, 1H, m;                                                  4.2 ppm, 1H, m; 3.8- 3.1 ppm,                                                 6H, m; 3.0 ppm, 3H, s; 3.05-                                                  2.6 ppm, 4H, m; 2.3 ppm, 2H,                                                  t; 1.8 ppm, 2H, m; 1.7 ppm,                                                   2H, s; 1.0 ppm, 3H, t; 12.7                                                   ppm, 1H exchangeable              25                                                                                ##STR98##    1                                                                                ##STR99##                                                                            0                                                                                ##STR100##    .sup.1 H NMR (CDCl.sub.3)                                                     salt 7.3 to 7.1 ppm, 4H, m;                                                   6.1 to 5.8 ppm, 1H, m; 5.4 to                                                 5.1 ppm, 2H, m; 4.5 ppm, 2H,                                                  d; 4.2 ppm, 1H, m; 3.95 ppm,                                                  1H, m; 3.7 to 3 ppm, 2H,                                                      m+1H, dd+ 2H, m+2H, m+1H, dd;                                                 2.75 ppm, 3H, s; 2.4 to 2.1                                                   ppm, 2H, m; 1.75 ppm, 2H, m;                                                  10.9 ppm, 1H exchangeable         26                                                                                ##STR101##   1                                                                                ##STR102##                                                                           0                                                                                ##STR103##    .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 7.2 ppm, 4H, m; 6.8 ppm,                                                 1H, m; 6.1 to 5.7 ppm, 2H,                                                    2d; 4.65 to 4.2 ppm, 1H, 2m;                                                  3.95 ppm, 1H, m; 3.7 to 3                                                     ppm, 2H+1H+2H+2H, m+dd+m+m;                                                   2.75 to 2.5 ppm, 3H, 2s; 2.25                                                 ppm, 2H,  m; 1.7 ppm, 2H, m;                                                  10.8 ppm, 1H exchangeable         27                                                                                ##STR104##   1                                                                                ##STR105##                                                                           0                                                                                ##STR106##    .sup.1 H NMR (CDCl.sub.3)                                                     base 8.4 ppm, 1H, dd; 7.95                                                    ppm, 1H, dd; 7.25 ppm, 1H,                                                    2s; 7.45 ppm, 1H, m; 7.4 to                                                   7.1 ppm, 4H, m; 4.55 and 3.6                                                  ppm, 1H, 2m; 3.56 ppm, 2H, s;                                                 3.05 ppm, 2H, m; 2.8 ppm, 3H,                                                 s; 2.5 to 2.1 ppm, 2H, m+2H,                                                  q; 2.1 to 1.5 ppm, 4H, m; 1.1                                                 ppm, 3H, 2t                       28                                                                                ##STR107##   1                                                                                ##STR108##                                                                           0                                                                                ##STR109##    .sup.1 H NMR (CDCl.sub.3                                                      +DMSO-d.sub.6) salt 6.8 ppm,                                                  2H, s; 6.7 ppm, 1H, d; 6.55                                                   ppm, 1H d; 5.9 ppm, 2H, s;                                                    4.15 ppm, 3H, q; 3.8 ppm, 1H,                                                 m; 3.6-3.2 ppm, 3H, m;                                                        3.15-2.7 ppm, 3H, m; 2.75                                                     ppm, 3H, s; 2.5 ppm, 2H, m;                                                   2.05 ppm, 2H, m; 1.75 ppm,                                                    2H, m; 1.25 ppm, 3H, t; 7.3                                                   ppm, 2H exchangeable              29                                                                                ##STR110##   1                                                                                ##STR111##                                                                           0                                                                                ##STR112##    .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 6.8 ppm, 1H, d; 6.7 ppm,                                                 1H, d; 6 ppm, 2H, 2s; 4.6 to                                                  3.5 ppm, 1H, 2m; 3.95 ppm,                                                    1H, m; 3.7 ppm, 8H, m; 2.8                                                    ppm, 3H, 2s, 2.4 a 2 ppm,                                                     2H+2H, q+m; 1.9 to 1.5 ppm,                                                   2H, m; 1 ppm, 3H,  t; 11.5 to                                                 11 ppm, 1H exchangeable           30                                                                                ##STR113##   1                                                                                ##STR114##                                                                           0                                                                                ##STR115##    .sup. 1 H NMR (DMSO-d.sub.6)                                                  base 8.4 ppm, 1H, dd; 7.95                                                    ppm, 1H, dd; 7.8 ppm, 1H, s;                                                  7.5 ppm, 3H, m; 7.25 ppm, 2H,                                                 m; 7.1 ppm, 1H, m; 4.55 and                                                   3.55 ppm, 1H, m; 3.5 ppm 2H,                                                  s; 3.05 ppm, 2H, m; 2.9 ppm                                                   3H, s; 2.1-2.4 ppm, 2H, m+2H,                                                 d; 1.5 to 2.1 ppm, 4H, m;                                                     1.15 ppm, 3H, td                  31                                                                                ##STR116##   0                                                                                ##STR117##                                                                           0                                                                                ##STR118##    .sup.1 H NMR (CDCl.sub.3)                                                     base 7.15 ppm, 4H, m; 4.55 to                                                 3.55 ppm, 1H, 2m; 3.2 to 3                                                    ppm, 5H, m; 3.0 to 2.9 ppm,                                                   2H, d; 3.85 ppm, 3H, d; 2.35                                                  ppm, 2H, q; 2.2 ppm, 2H, q;                                                   2.05 a  1.5 ppm, 4H, m; 1.15                                                  ppm, 3H, dd                       32                                                                                ##STR119##   2                                                                                ##STR120##                                                                           0                                                                                ##STR121##    .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 8.4 ppm, 1H, d, 8.15                                                     ppm, 1H, d; 8.1 ppm, 1H, s;                                                   7.6 to 7.9 ppm, 4H, m; 7.35                                                   ppm, 1H, dd; 4.15 ppm, 1H, m,                                                 .05 ppm, 2H, q; 3.6 ppm, 2H,                                                  m; 2.9 to 3.5 ppm, 6H, m; 2.7                                                 ppm, 3H, s; 2.15 ppm, 2H, m;                                                  1.75 ppm, 2H, m; 1.2 ppm, 3H,                                                 t; 10.6 ppm, 1H exchangeable      33                                                                                ##STR122##   2                                                                                ##STR123##                                                                           0                                                                                ##STR124##    .sup.1 H NMR (CDCl.sub.3)                                                     salt 8.45 ppm, 1H, dd; 8.00                                                   ppm, 1H, s; 7.95 ppm, 1H, m;                                                  7.65 to 7.85 ppm, 2H, m; 7.55                                                 ppm, 1H, s; 7.5 ppm, 1H, d;                                                   7.2 ppm, 1H, dd; 4.8 ppm, 1H,                                                 m; 3.7 ppm, 2H, d; 3.15 to                                                    3.5 ppm, 4H, m; 2.95 ppm, 3H,                                                 s 2.85 ppm, 2H, d; 2.45 to                                                    2.7 ppm, 2H, m 2.35 ppm, 2H,                                                  q; 1.8 ppm, 2H, d; 1.1 ppm,                                                   3H, t; 12.5 ppm, 1H                                                           exchangeable                      34                                                                                ##STR125##   1                                                                                ##STR126##                                                                           0                                                                                ##STR127##    .sup.1 H NMR (CDCl.sub.3)                                                     salt 7.15 ppm, 2H, m; 6.9                                                     ppm, 1H, t; 6.8 ppm, 1H, d;                                                   5.55 ppm, 1H, m; 4.85 ppm,                                                    1H, m; 4.10 ppm, 1H, m;                                                       3.65-3.3 ppm, 3H, m; 3.25-2.8                                                 ppm, 4H, m; 2.95 ppm, 3H, s;                                                  2.65 ppm, 2H, m; 2.35 ppm,                                                    2H, q; 1.8 ppm, 2H, m; 1.15                                                   ppm, 3H, t; 12.9 ppm, 1H                                                      exchangeable                      35                                                                                ##STR128##   2                                                                                ##STR129##                                                                           0                                                                                ##STR130##    .sup.1 H NMR (CDCL.sub.3)                                                     salt 7.2+7.05 ppm, 2H+2H,                                                     m+m; 4.8 ppm,  1H, m; 3.6                                                     ppm, 3H, m; 3.4 ppm, 1H, dd;                                                  3.1 ppm, 2H, m; 2.9 ppm, 3H,                                                  s; 2.45 to 2.55 ppm, 5H, m;                                                   2.35 ppm, 4H,  q+m; 1.75 ppm,                                                 2H, m; 1.1 ppm, 3H, t; 12.5                                                   ppm, 1H exchangeable              36                                                                                ##STR131##   1                                                                                ##STR132##                                                                           0                                                                                ##STR133##    .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 7.5 ppm, 2H, d 7.3 to                                                    7.1 ppm, 6H, m+ 1H                                                            exchangeable; 6.95 ppm, 1H,                                                   t; 3.95 ppm, 2H, m; 3.7 to                                                    2.9 ppm, 8H, m; 2.85 ppm, 3H,                                                 s; 2.25 to 13.75 ppm, 4H, m;                                                  8.4 ppm, 1H exchangeable          37                                                                                ##STR134##   1                                                                                ##STR135##                                                                           0                                                                                ##STR136##    .sup.1 H NMR (DMSO-d.sub.6)                                                   salt 7.2 ppm, 4H, m; 6.35                                                     ppm, 1H exchangeable; 4.35                                                    ppm, 1H, m; 3.95 ppm, 1H, m;                                                  3.7 to 3.0 ppm,                                                               10H, m+dd+q+m+dd+m; 2.7 ppm,                                                  3H, s 2.6 to 1.65 ppm, 4H                                                     m+m; 1.05 ppm, 3H, t; 10.85                                                   ppm, 1H exchangeable              38                                                                                ##STR137##   1                                                                                ##STR138##                                                                           0                                                                                ##STR139##    .sup.1 H NMR (CDCl.sub.3)                                                     base 7.3 ppm, 5H, m; 7.3 to 7                                                 ppm, 4H, m; 4.7 ppm, 1H                                                       echangeable; 4.45 ppm, 2H, d;                                                 4.2 ppm, 1H, m; 3.7 ppm, 1H,                                                  m; 3.4 ppm, 1H, dd; 3.05 ppm,                                                 2H, d; 2.9 to 2.5 ppm, 3H,                                                    m+d+d; 2.8 ppm, 3H, s 2.2                                                     ppm, 2H, t; 1.9 to 1.6 ppm,                                                   4H, m                             39                                                                                ##STR140##   1                                                                                ##STR141##                                                                           0                                                                                ##STR142##    NMR (DMSO-d.sub.6) salt 7.2                                                   ppm, 4H, m; 5.1 ppm and 5                                                     ppm, 2H, 2s; 3.95 ppm, 1H, m;                                                 2.55 ppm, 3H, s; 3.7 to 3.1                                                   ppm, 6H, 4m; 2.8 ppm, 3H, s;                                                  2.3 ppm, 2H, m; 1.95 ppm, 3H,                                                 s; 1.75 ppm, 2H, m                40                                                                                ##STR143##   1                                                                                ##STR144##                                                                           0                                                                                ##STR145##    NMR (CDCl.sub.3) base 8.2 to                                                  8.05 ppm, 1H, 2s; 7.2 ppm,                                                    2H, m; 7.1 ppm, 2H, m; 4.3                                                    and 3.35 ppm, 1H, 2m; 3.7                                                     ppm, 1H, m; 3.4 ppm, 1H, dd;                                                  3.1 ppm, 2H, m; 2.9 and 2.85                                                  ppm, 3H, 2s; 2.8 ppm, 2H, m;                                                  2.6 ppm, 1H, dd; 2.03 to 1.1                                                  ppm, 6H, m                        41                                                                                ##STR146##   1                                                                                ##STR147##                                                                           0                                                                                ##STR148##    NMR (DMSO d.sub.6) salt 11.3                                                  ppm, 1H exchanged with                                                        D.sub.2 O, m; 7.3 to 7 ppm,                                                   4H, m; 4.55 and 3.9 ppm, 1H,                                                  2m; 4.15 et 4.05 ppm, 2H, 2s;                                                 4 ppm, 1H, m; 3.7 to 3 ppm,                                                   11H, m+dd+m+s+dd+m                42                                                                                ##STR149##   1                                                                                ##STR150##                                                                           0                                                                                ##STR151##    NMR (DMSO-d.sub.6) salt 11.05                                                 ppm, 1H exchangeable; 7.3 to                                                  7 ppm, 5H, 2m; 4.8 ppm, 1H,                                                   d; 4.05 ppm, 1H, dd; 4.2 ppm,                                                 1H, m; 3.95 ppm, 1H, m; 3.7                                                   to 3 ppm, 8H, m+dd+2m+dd;                                                     2., 8 ppm, 3H, s; 2.3 ppm,                                                    2H, m; 1.75  ppm, 2H, m           43                                                                                ##STR152##   0                                                                                ##STR153##                                                                           0                                                                                ##STR154##    NMR (DMSO-d.sub.6) salt 7.15                                                  ppm, 4H, m; 6.6 ppm, 2H, s;                                                   3.85 ppm, 1H, m; 3.75 ppm,                                                    2H, d; 3.25 ppm, 1H, m; 3.15                                                  to 2.75 ppm, 6H, m; 2.7 ppm,                                                  3H, s; 2.2 ppm, 2H, m; 1.95                                                   to 1.5 ppm, 5H, m; 0.9 ppm,                                                   6H, d; 4.5 ppm, 2H, s (very                                                   level and very broad)                                                         exchangeable                      44                                                                                ##STR155##   0                                                                                ##STR156##                                                                           0                                                                                ##STR157##    NMR (CDCl.sub.3) base 7.15                                                    ppm, 4H, m; 4.2 to 3.8 ppm,                                                   1H, m; 4.0 ppm, 2H, t; 3.3 to                                                 3.0 ppm, 5H, m; 2.9 ppm, 2H,                                                  dd; 2.8 ppm, 3 H, s; 2.1 ppm,                                                 2H, m; 1.9 to 1.5 ppm, 6H, m;                                                 .95 ppm, 3H,                      __________________________________________________________________________                                                t                             

EXAMPLE 45 Pharmacological Study

a) "Tail-Flicks" test on rats

The 5HT_(1A) receptor antagonism of the compounds of the invention wasdemonstrated by the method according to Millan et. al. (Neurosci. Lett.(1989), 107, p. 227-232).

Subcutaneous injection of rats with 8-OH-DPAT spontaneously induces tailmovements ("Tail-Flicks"). These movements are reduced in a specificmanner by 5HT_(1A) receptor antagonists. The ED₅₀ values, that is to saythose amounts of the compounds of the invention that reduce 8-OH-DPATaction by 50%, are listed in Table II.

                  TABLE II                                                        ______________________________________                                        COMPOUND EXAMPLE  ED.sub.50 mg/Kg - s.c. route                                ______________________________________                                         8                1.25                                                         9                0.31                                                        11                2.50                                                        12                2.50                                                        13                1.25                                                        14                0.02                                                        15                1.25                                                        21                0.63                                                        22                1.25                                                        23                2.50                                                        24                1.25                                                        28                2.50                                                        31                0.31                                                        42                1.25                                                        44                2.5                                                         ______________________________________                                    

b) Sigma binding test (in vitro)

The affinity of the compounds of the invention to the sigma receptor inbrain tissue is evaluated by the degree of inhibition of the binding ofa sigma site radioligand in in vitro competition experiments.

The experiment protocol used is that described by WEBER et at. Proc.Nat. Acad. Sci. USA, (1986), 83, 8784-8788.

The ligand is 1,2-di-(2-[5-³ H]tolyl)guanidine (Dupont de Nemours--55Ci/mmol) at a final concentration of 2 nM.

The membrane preparation is a suspension of central nervous systemmicrosomes of a guinea pig used at a final concentration of 0.5 mg ofprot/ml.

The non-specific fixation is determined in the presence of 10 μM ofhaloperidol.

The results, given in Table III, to illustrate the invention areexpressed at IC₅₀ =K.0.5 (M)

                  TABLE III                                                       ______________________________________                                        Inhibition of [3H] ditolylguanidine binding                                   COMPOUND EXAMPLE    IC.sub.50 in M                                            ______________________________________                                         9                  3.10.sup.-8                                               12                  3.10.sup.-8                                               15                  1.10.sup.-7                                               18                  8.10.sup.-8                                               19                  3.10.sup.-8                                               24                  2.10.sup.-8                                               31                  2.10.sup.-7                                               42                  5.10.sup.-8                                               43                  4.10.sup.-9                                               44                  4.10.sup.-8                                               ______________________________________                                    

EXAMPLE 46 Pharmaceutical Composition

    ______________________________________                                        Tablets each containing 5 mg of propyl N-[1-(benzocyclo-                      buten-1-ylmethyl)-piperid-4-yl]-N-methylcarbamate                             hydrochloride (P.B.M.P.M.C.)                                                  ______________________________________                                        P.B.M.P.M.C.       5 g                                                        wheat starch      100 g                                                       cornstarch        20 g                                                        magnesium stearate                                                                              20 g                                                        talc              20 g                                                        ______________________________________                                    

for 1000 tablets each containing 5 mg of active ingredient.

We claim:
 1. A compound selected from these of formula I ##STR158## inwhich: m represents zero, 1, 2, 3, or 4,n represents 1 and p representzero, 1 or 2, W represents oxygen, --NH--, or a single bond, Rrepresents: 4-oxo-4H-chromen-2-yl of formula F: ##STR159## in which: R₇,R₈ and R₉, which may be the same or different, each represents hydrogen,halogen, (C₁ -C₆) -alkyl or -alkoxy, polyhalogenated (C₁ -C₆) alkyl,hydroxy, or R₇ and R₈ or R₈ and R₉ together form methylenedioxy,ethylenedioxy, furan ring or dihydrofuran ring and R₁ representshydrogen or (C₁ -C₆) alkyl, or carbocyclic aryl; R₂ represents hydrogen,(C₁ -C₆) alkyl, (C₂ -C₆) alkenyl, (C₄ -C₇) cycloalkyl, benzyl or phenyl(each optionally substituted by one or more halogen, hydroxy, (C₁ -C₆)-alkyl or -alkoxy, (C₇ -C₁₂) aralkyl, (C₂ -C₇) alkoxyalkyl orpolyhalogenated (C₁ -C₆) alkyl, the optical isomers thereof and theaddition salts thereof with a pharmaceutically acceptable organic ormineral acid.
 2. A compound of claim 1 which is:N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylpropionamide,the optical isomers thereof and the addition salts thereof with apharmaceutically-acceptable organic or mineral acid.
 3. A compound ofclaim 1 which is:N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylbutanamide,the optical isomers thereof and the addition salts thereof with apharmaceutically-acceptable organic or mineral acid.
 4. A compound ofclaim 1 which is:N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylacetamide,the optical isomers thereof and the addition salts thereof with apharmaceutically-acceptable organic or mineral acid.
 5. A compound ofclaim 1 which is:N-{1-[(4-oxo-4H-chromen-2yl)-methyl]-piperid-4-yl}-N-ethylpropionamide,the optical isomers thereof and the addition salts thereof with apharmaceutically-acceptable organic or mineral acid.
 6. A compound ofclaim 1 which is:N-{1-[2-(4-oxo-4H-chromen-2yl)-ethyl]-piperid-4-yl}-N-methylpropionamide,the optical isomers thereof and the addition salts thereof with apharmaceutically-acceptable organic or mineral acid.
 7. A compound ofclaim 1 which is: ethylN-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylcarbamate,the optical isomers thereof and the addition salts thereof with apharmaceutically-acceptable organic or mineral acid.
 8. A compound ofclaim 1 which is:N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylisobutylamide,the optical isomers thereof and the addition salts thereof with apharmaceutically-acceptable organic or mineral acid.
 9. A compound ofclaim 1 which is:N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylpropionamidehydrochloride.
 10. A compound of claim 1 which is:N-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-ethylpropionamidehydrochloride.
 11. A compound of claim 1 which is:N-{1-[2-(4-oxo-4H-chromen-2yl)ethyl]-piperid-4-yl}-N-methylpropionamidehydrochloride.
 12. A compound of claim 1 which is: ethylN-{1-[(4-oxo-4H-chromen-2-yl)-methyl]-piperid-4-yl}-N-methylcarbamatehydrochloride.
 13. A compound of claim 1 which is:N-{1-[(4-oxo-4H-chromen-2yl)-methyl]-piperid-4-yl}-N-methylisobutylamidehydrochloride.
 14. A method for treating a living animal body afflictedwith a disease resulting from pain, stress, migraine, anxiety,depression and schizophrenia, comprising the step of administering anamount of a compound of claim 1 which is suitable for the alleviation ofthe said condition.
 15. A pharmaceutical composition containing asactive ingredient an effective amount of a compound of claim 1, alone orin combination with one or more physiologically tolerable inertcarriers.